Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](O)=[O:22].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(OCC)(=O)C.CN(C)C=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)=[O:22]
Reactant: O=C(O)c1cccs1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.40 g), thiophene-2-carboxylic acid (0.28 g), ethyldiisopropylamine (0.75 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.82 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:97-3:7) to give the title compound (510 mg, yield 83%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>O>[C:2]([NH:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:1]
Reactant: Nc1cccc(O)c1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O
Product: CC(=O)Nc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Acetic anhhydride (21.2 ml, 220 mmol) was slowly added to a suspension of m-aminophenol (24.0 g, 220 mmol) in 60% of crushed ice and 60 ml of cold water. The reaction mixture was vigorously stirred for 30 minutes. The white precipitate was filtered, washed with cold water, and air-dried to give 30.5 g (92%) of pure 3-acetamidophenol, m.p. 147°-149° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=O)=O.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1OB(O)O.C(N(CC)CC)C.O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9][N:8]=1
Reactant: COC(=O)c1ccc2ccnc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: OB(O)Oc1c(F)cc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2ccnc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (250 mg), 2,4,6-trifluorophenylboric acid (184 mg), tetrakis(triphenylphosphine)palladium (22 mg), triethylamine (189 mg), and 1,4-dioxane (15 mL) was heated under stirring in an oil bath at 95° C. for 18 hours. The reaction mixture was returned to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (228 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].O[CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>O>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][CH2:17][C:13]1[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])=[O:24]
Reactant: CC(C)(C)C(=O)NCO
Reactant: Cc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(CNC(=O)C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Cool sulfuric acid (3.67 mL) to 0° C., and add 2-methylbenzoic acid (500 mg, 3.67 mmol, 1.0 equiv) and N-(hydroxymethyl)-2,2-dimethylpropanamide (506 mg, 3.86 mmol, 1.05 equiv). Allow the mixture to warm to room temperature, and stir overnight. Dilute with water (25 mL) and extract with EtOAc (50 mL). Dry the organic layer over MgSO4, filter, and concentrate under reduced pressure to give the crude compound. Purify the material by reverse-phase HPLC on an XBridge Prep C18 5 μM OBD 30×75 mm column, eluting with a gradient of 5-50% (0.1% TFA in acetonitrile) in (0.1% TFA in water) to give the title compound (255 mg, 28%). 1H NMR (DMSO-d6, 400 MHz): δ 12.76 (s, 1H), 8.09 (t, 1H, J=6.0 Hz), 7.67 (d, 1H, J=1.6 Hz), 7.25 (dd, 1H, J=8.0, 1.6 Hz), 7.21 (d, 1H, J=8.0 Hz), 4.22 (d, 2H, J=6.0 Hz), 2.46 (s, 3H), 1.10 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][CH:15]=[N:14][CH:13]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[S:16][CH:15]=[N:14][CH:13]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cncs1
Solvent: CCO
Product: COc1cc(N)ccc1-c1cncs1
Yield: 92 %

Procedure:
A suspension of 5-(2-methoxy-4-nitro-phenyl)-thiazole (160 mg, 0.68 mmol and stannous dichloride (655 mg, 3.39 mmol) in ethanol (10 mL) was stirred at reflux temperature for 75 min. The yellow solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. This solution is washed successively with 2N aqueous sodium hydroxide and with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residual material was triturated with dichloromethane, insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to afford the title compound (128 mg, 92%) as orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[S:27]([CH3:26])(=[O:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(Nc1ccc(F)cc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCC(c1cccnc1)N(c1ccc(F)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 5.5 g. portion of 3-[1-(4-fluorophenylamino)pentyl]pyridine was dissolved in 40 ml. of dichloromethane, and to it were added 3.4 g. of potassium carbonate and 1.9 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature overnight, and then an additional 1.9 ml. of methanesulfonyl chloride was added and the mixture was stirred for 3 days with gentle heating. It was then cooled and extracted with aqueous sodium bicarbonate solution, and then with water, and it was then dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in chloroform and was purified over silica gel, eluting with chloroform, to obtain 0.7 g. of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][N:27]=1)[C:12]([NH:14][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1)=[O:13].[CH3:28][C:29]([CH3:58])([O:31][C:32](=[O:57])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[C:51](O)=[O:52])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:51]([C:50]2[CH:49]=[C:48]([CH2:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][C:32]([O:31][C:29]([CH3:58])([CH3:30])[CH3:28])=[O:57])[CH:56]=[CH:55][CH:54]=2)=[O:52])=[C:3]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[NH:14][C@@H:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH:25]=[CH:26][N:27]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 65 °C
Yield: 66.6 %

Procedure:
To a solution of (S)-2-(2-amino-5-chlorophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 237b (1.02 g, 2.7 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid 251c (1.19 g, 2.7 mmol), DIPEA (1.04 g, 8.1 mmol) and DMAP (190 mg, 1.55 mmol) in DMF (20 ml) was added HATU (1.13 g, 2.97 mmol). The reaction mixture was heated at 65° C. for 24 hours, then cooled and concentrated. The residue was combined with another run (0.28 mmol scale), dissolved in DCM (150 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (10% to 30% EtOAc in DCM) gave the title compound (1.44 g).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc2ncccc2c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C(Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A solution of methyl (S) 2-(N-boc-amino)-3-quinolin-6-yl-propionate [3.8 g, Reference Example 20(a)] in ethanol (100 ml) at 60° C. was treated with ammonium formate (10 g) and 10% palladium on charcoal (500 mg). After stirring at 60° C. further ammonium formate (about 5 g) and palladium on charcoal (about 250 mg) were added, and this was repeated at 30 minute intervals for a further 2 hours, at which time TLC analysis indicated the reaction was complete. After cooling to room temperature the mixture was filtered through Celite to remove spent catalyst, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (200 ml) and sodium bicarbonate solution (200 ml). The organic phase was dried and evaporated to give the title compound (3.8 g) as a colourless oil which slowly crystallised on standing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[C:41]1([NH:40][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[Se:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)c1ccccc1[Se]Cc1ccccn1
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccccc1[Se]Cc1ccccn1

Procedure:
To a solution of 7 g (0.024 mol) 2-(2-picolylseleno)benzoic acid (from Example 1) and 2.4 g (0.024 mol) triethylamine in 40 ml dichloromethane which has been cooled to 0°-5° C. is added 6 g (0.024 mol) bis(2-oxo-3-oxazolidinyl)phosphoryl chloride in solid form as one portion. After stirring for 20 minutes a solution of 2.2 g (0.024 mol) aniline in 5 ml dichloromethane and a solution of 2.4 g (0.024 mol) triethylamine in 5 ml dichloromethane and a solution of 2.4 g (0.024 mol) triethylamine in 5 ml dichloromethane are added dropwise within 5 min, after 16 h at room temperature the reaction mixture is washed with 100 ml water. The organic phase is extracted successively with 100 ml 10% NaHCO3 solution, 100 ml 10% citric acid and 100 ml water. The organic phase is dried over sodium sulfate and the solvent removed under water pump vacuum. The solid crude product (6.3 g) is recrystallized from 35 ml 2-propanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH:11]([C:13](=[O:18])[NH:14][CH:15]2[CH2:17][CH2:16]2)[OH:12])[CH2:10][CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([CH:11]([OH:12])[C:13]([NH:14][CH:15]2[CH2:16][CH2:17]2)=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)NC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(C(O)C(=O)NC2CC2)CC1

Procedure:
A solution of [1-(cyclopropylcarbamoylhydroxymethyl)cyclopropyl]carbamic acid tert-butyl ester in CH2Cl2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and chased with toluene to yield 2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C[N+](C)(C)C.[OH-].[C:12](#[N:15])[CH:13]=[CH2:14].Cl>O>[C:12]([CH2:13][CH2:14][NH:1][CH2:2][C:3]([OH:5])=[O:4])#[N:15]
Reactant: C=CC#N
Reactant: NCC(=O)O
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: O
Product: N#CCCNCC(=O)O
Temperature: 10 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Glycine (5 g, 67 mmol) was suspendeed in water (10 cm3) and TMAH (25% in water, 24.3 g, 67 mmol) was added slowly, keeping the temperature at <30° C. with an ice-bath. The mixture was then cooled to 10° C. and acrylonitrile (3.89 g, 73 mmol) was added. The mixture was stirred overnight, and allowed to warm to room temperature slowly. The mixture was then neutralized with HCl (6M, 11.1 cm3), concentrated to 15 cm3 and diluted to 100 cm3 with EtOH. The solid precipitated was collected by filtration, dissolved in hot water (6 cm3) and re-precipitated with EtOH (13 cm3) to give 2-(2-cyanoethylamino)acetic acid (5.94 g, 69.6%) as a white solid, mp 192° C. (lit mp 190-191° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O.C([BH3-])#N.[Na+].CO>CO.C(O)(=O)C.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:25])([F:26])[F:27])[CH:16]=3)[CH:31]([CH3:33])[CH3:30])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)C(F)(F)COc1cccc(CNCCc2c[nH]c3cc(Cl)ccc23)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(CCc1c[nH]c2cc(Cl)ccc12)Cc1cccc(OCC(F)(F)C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Combine N-(2-(6-Chloro-1H-indol-3-yl)ethyl)-3-(2,2,3,3,3-pentafluoropropoxy)benzylamine (254 mg, 0.59 mmol) in 20 mL of 95:5 methanol-acetic acid, treat with acetone (441 μL, 5.9 mmol) followed by sodium cyanoborohydride in portions (148 mg, 2.3 mmol). Stir the reaction mixture at 50° C. overnight; then at room temperature for an additional 2 days. Remove the solvent in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 4% methanol in dichloromethane to give the title compound as a colorless oil. Dissolve the oil (237 mg, 0.49 mmol) in methanol (15 mL) and treat with a solution of ammonium chloride (27 mg, 0.49 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before concentrating it to a tacky white solid. Dissolve the tacky solid in 10 mL of 1:1 acetonitrile-water and lyophilize to give 241 mg (96%) of the title compound as the hydrochloride: mp: 77.0–80.2° C.; 1H NMR (400 MHz, methanol-d4): 7.31 (br t, 1H, J=7.8 Hz), 7.26–7.21 (m, 1H), 7.16 (br d, 1H, J=8.4 Hz), 7.15–7.07 (m, 2H), 7.05–6.95 (m, 2H), 6.83 (dd, 1H, J=8.0, 2.0 Hz), 4.52 (t, 2H, J=12.8 Hz), 4.12 (br s, 2H), 3.53 (br s, 1H), 3.11 (br s, 2H), 2.89 (br s, 2H), 1.27 (br s, 6H); MS (APCI): m/e 475.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[OH:23][C:5]1[C:6]([CH2:20][CH2:21][CH3:22])=[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:12]([C:13]3[NH:26][N:25]=[N:24][N:14]=3)[CH:11]=2)[CH:18]=[CH:19][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(C#N)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(-c3nnn[nH]3)c2)ccc(C(C)=O)c1O
Yield: 82.8 %

Procedure:
A mixture of 8.25 g 3-[(4-acetyl-3-hydroxy-2-propyl phenoxy)methyl]benzonitrile, 5.20 g sodium azide and 4.30 g ammonium chloride in 125 mL anhydrous dimethylformamide was stirred and heated at 120° for 6 hr. The solvent was removed in vacuo and the residue was treated with 250 mL water and acidified with 10 mL 6N hydrochloric acid. The resulting solid was recrystallized from ethanol-water to give 7.78 g, mp 194°-195° of 1-[2-hydroxy-3-propyl-4-[[3-(1H-tetrazol-5-yl)phenyl]methoxy]phenyl]ethanone.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Cl[C:19]1[C:24]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:33])[N:22]=[C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:20]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:19]1[C:24]([CH:25]([CH2:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH3:33])[N:22]=[C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:20]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCc2ccccc2C1
Temperature: 100 °C
Yield: 93.4 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (0.190 mL, 1.5 mmol) and triethylamine (0.277 mL; 2 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL) and heated in a sealed tube to 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.194 g (93%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[NH:26][C:27]([C:29]2[N:30]=[N:31][N:32]([OH:34])[CH:33]=2)=[O:28])=[CH:20][CH:19]=1.CC(C)=O.CCN(CC)CC>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[NH:26][C:27]([C:29]2[N:30]=[N:31][N:32]([O:34][CH2:2][C:3]3[O:4][C:5](=[O:9])[O:6][C:7]=3[CH3:8])[CH:33]=2)=[O:28])=[CH:22][CH:23]=1
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: Cc1oc(=O)oc1CCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1COn1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3Cl)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (14.9 mg, 100 μmol) was added to a solution of (R)-3-[N-(2′,5′-dichlorobiphenyl-4-ylmethyl)-N′-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound (10.0 mg, purity 99%) as a white solid. MS m/z [M+H]+ calc'd for C24H21Cl2N5O8, 578.08. found 578.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[C:4]([N+:41]([O-:43])=[O:42])[CH:3]=1.[CH2:44](O)[CH3:45].C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:44][CH3:45])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=2)=[C:4]([N+:41]([O-:43])=[O:42])[CH:3]=1
Reactant: Cc1onc(-c2ccccc2O)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Reactant: CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the solution of N-(4-chloro-5-(4-(3-(2-hydroxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)-2-nitrophenyl)-4-(dimethylamino)benzamide (Example 117, 17 mg, 0.028 mmol), ethanol (2.461 μL, 0.042 mmol) and tri-n-butyl phosphine (10.40 μL, 0.042 mmol) in THF (2 mL) at 0° C. was added DIAD (8.19 μL, 0.042 mmol). The reaction mixture was stirred at 0° C. for 3 min. and at RT overnight.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]([F:25])([F:24])[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12](Cl)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=1.O>CN(C=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]1[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:7]([F:25])([F:24])[F:6])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(CC)CC)cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Diethylamine (2.1 ml, 0.020 mol) was slowly added to a solution of 3.0 g (0.009 mol) of product of Example 19 in 15 ml of DMF and stirred overnight. Reaction mixture was poured into water, extracted with ether, washed with water, dried (MgSO4) and concentrated. The residue was kugelrohr distilled twice at 28 Pa, pot temperature 76° C., to afford 2.06 g (63.2%) of product as a yellow oil, nD25 1.4593.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].[H-].[Na+].Cl([F:33])(=O)(=O)=O.C(Cl)Cl>CN(C)C=O.Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:33])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)-isoindoline (1.0 g. 2.8 mmol) in dimethylformamide (10 mL) is added sodium hydride (112 mg, 2.8 mmol, 60%) at room temperature. After about 30 minutes, perchloryl fluoride (5 mmol) is bubbled into the mixture . The mixture is stirred with methylene chloride (10 mL) and IN hydrochloric acid (10 mL) for one hour. The organic layer is separated 30 and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.