Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:40][CH:39]=2)(C(OCC=C)=O)[C:24]([O:26]CC=C)=[O:25])=[CH:17][CH:16]=1)=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:47][O:46][C:44]([C:41]1[CH:40]=[CH:39][C:38]([CH2:37][CH2:36][CH:23]([CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:13]([O:12][CH3:11])=[O:14])=[CH:20][CH:19]=2)[C:24]([OH:26])=[O:25])=[CH:43][CH:42]=1)=[O:45]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(CCc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
At room temperature, a solution of 20.48 ml (146.9 mmol) of triethylamine and 4.2 ml (111.29 mmol) of formic acid in 50 ml of dioxane is added to a solution of 22.64 g (44.52 mmol) of diallyl bis{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate, 0.82 g (3.12 mmol) of triphenylphosphine and 200 mg of palladium acetate in 250 ml of dioxane. The reaction mixture is then stirred at 100° C. overnight. After the reaction has gone to completion, the reaction solution is cooled and the solvent is removed under reduced pressure. The residue obtained is taken up in water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 10.4 g (27.1 mmol, 61% of theory) of a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:27][N:26]=3)([CH3:24])[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[O:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:24][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:13]=2)=[CH:19][CH:18]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][N:26]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(C)(c1ccc(-c2cc(CBr)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C(C)(c1ccc(-c2cc(CN3CCOCC3)no2)cc1)c1ccc(OCc2ccccn2)cn1
Temperature: 50 °C

Procedure:
Morpholine (17.5 μL, 0.200 mmol) was added to a stirred solution of 1e (49.0 mg, 0.100 mmol) and cesium carbonate (130 mg, 0.400 mmol) in DMF (1.00 mL) at rt. The resulting mixture was heated to 50° C. for approximately 1 h, cooled to rt, and then filtered through a short column of CELITE® eluting with EtOAc. The filtrate was concentrated in vacuo and the crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 1f. m/z (ES) 499 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:32])[N:9]([CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:15])=[O:4].[CH3:33][NH:34][CH3:35].Cl>O1CCCC1.C(OCC)(=O)C.CCOCC>[ClH:1].[CH3:33][N:34]([CH3:35])[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=[O:32])[N:9]([CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH2:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:15])=[O:4]
Reactant: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
A mixture of 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.07 g, 2.34 mmol) and N,N-dimethylamine (2.0 M in methanol, 3.5 mL, 7.0 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give an oil. The oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 7:3) to give a white solid. To a solution of the solid in ethyl acetate (10 mL) was added hydrogen chloride in ether (1N, 4 mL). The slurry was filtered and washed with ether to give 2-(dimethylamino)-N-(2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide hydrochloride as a white solid (0.52 g, 44%); mp 100-102° C.; 1H NMR (DMSO-d6) δ10.63 (s, 1H), 10.27 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.84 (t, J=7.7 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 2H), 5.63-5.57 (dd, J=6.0 and 8.8 Hz, 1H), 4.19 (b, 2H), 3.99 (q, J=6.9 Hz, 2H), 3.77-3.67 (m, 1H), 3.74 (s, 3H), 3.52-3.42 (dd, J=6.1 and 18.1 Hz, 1H), 2.84 (s, 6H), 2.12 (s, 3H), 1.30 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ205.81, 167.32, 167.14, 164.84, 148.49, 147.76, 135.85, 134.29, 131.74, 131.48, 127.70, 119.48, 119.27, 119.09, 112.19, 111.76, 63.76, 58.32, 55.48, 48.90, 44.27, 43.47, 29.87, 14.69; Anal. Calcd. For C25H30N3O6Cl: C, 59.58; H, 6.00; N, 8.34; Cl, 7.03. Found: C, 59.18; H, 6.03; N, 8.14; Cl, 6.68.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[CH:45]=[C:44]([C:46](O)=O)[C:43]([C:49]([F:52])([F:51])[F:50])=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:46]([C:44]2[C:43]([C:49]([F:52])([F:50])[F:51])=[N:42][N:41]([CH3:40])[CH:45]=2)[O:16][N:15]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cn(C)nc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.0194 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.88 (d, J=1.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 4.01 (s, 3H), 2.96 (t, 2H), 1.82-1.67 (m, 2H), 1.03 (t, 3H); MS (ES) m/z 449 (M+1).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:7]([O:25][CH3:26])=[C:8]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=1)[CH3:5])=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][CH:4]([C:6]1[C:7]([O:25][CH3:26])=[C:8]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:15]2)[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=1)[CH3:5]
Reactant: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)N)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-[3-(1-azidoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate (0.084 g, 0.22 mmol) in THF (1 mL)/water (0.2 mL) was added 1.0 M trimethylphosphine in THF (0.33 mL, 0.33 mmol) at room temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give the desired product to be used in the next step without further purification.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[OH:12][C:2]1[CH:3]=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cnc2ccsc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cnc2ccsc2c1
Temperature: 0 °C

Procedure:
To a solution of 6-aminothieno[3,2-b]pyridine (2.5 g, 16.6 mmol) in water (22 ml) containing concentrated sulfuric acid (4.15 ml) and cooled at 0° C. was added dropwise with vigorous stirring a solution of sodium nitrite (1.26 g, 18.3 mmol) in water (7 ml) to give a copious yellow precipitate. This slurry was pipetted dropwise into 5% sulfuric acid (110 ml) maintained at 110° C. After an additional hour, the solution was cooled to room temperature and washed with methylene chloride. This aqueous solution was made basic with sodium hydroxide and washed again with methylene chloride to remove any unreacted starting material. The aqueous solution was then made neutral with hydrochloric acid and the precipitated product was extracted into chloroform/methanol, dried over anhydrous sodium sulfate and filtered through a pad of charcoal and the solvents were evaporated to give product (2.2 g) which was purified by crystallization from hot ethyl acetate/methanol to give pure product (1.81 g, 72% yield), m.p. 228°-230 ° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:10]#[N:11]>>[N+:1]([C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:7]([O:6][CH3:5])=[CH:8][C:9]=1[C:10]#[N:11])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C#N)cc1OC
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a nitric acid (40 mL) in ice bath was added 3,4-dimethoxybenzonitrile (5.0 g, 30.6 mmol) and was allowed to stir for 2 hours. Then the solution was gradually returned to room temperature. To this solution was added ice (200 mL) to get light yellow precipitate which was then collected by filtration to give 6.25 g (98%) of 2-nitro-4,5-dimethoxybenzonitrile. 1H NMR (100 MHz, DMSO-d6): δ3.69 (s, 3H, CH3), 3.90 (s, 3H, CH3), 7.53 (s, 1H, Ar--H), 7.75 (s, 1H, Ar--H). ms: m/z 208 (M+), 192 (M+ -16), 178 (M+ -30), 162 (M+ -46).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)cc1
Temperature: 110 °C
Yield: 72.8 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), [4-(methyloxy)phenyl]boronic acid (78 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 110° C. for 3 h. The resulting yellow slurry was diluted with ethanol then evaporated to dryness under reduced pressure. The residue was triturated from dichloromethane then the decanted solution was applied directly to a standard stock silica column (Analogix SF25-40 g) and eluted first with 100% ethyl acetate for 5 min and then with 7% methanol in dichloromethane. The combined desired fractions were evaporated to a colorless oil that was crystallized from hexanes/ethyl acetate to afford the title compound as a white solid (78 mg, 72.2%). MS(ES)+ m/e 419.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:39])[C:12]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]3[O:25][C:26]([C:29](O)([CH3:37])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1.[N-:40]=[N+]=[N-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:39])[C:12]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]3[O:25][C:26]([C:29]([NH2:40])([CH3:37])[CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](NC(=O)c1cc(-c2ccc(C(C)(O)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)c1cc(-c2ccc(C(C)(N)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
To a solution of Example 50 (0.080 g, 0.15 mmol) in 1 mL CHCl3 was added a suspension of sodium azide (0.094 g, 1.45 mmol) in TFA (0.06 mL, 0.73 mmol). The solution progressively turned dark over 1 h to afford a mixture of desired product and a byproduct resulting from dehydration. Concentrated and used as is in next reaction. LCMS [M+H]+=575.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:25](=[O:37])[NH:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[N:23]=3)[CH:20]=2)[CH:12]=[N:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl>Cl>[NH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:37])[NH:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:8])=[O:7])[CH:14]=[N:13][CH:12]=3)=[CH:20][N:19]2[N:21]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2ccc3nc(NC(=O)NCCNC(=O)OC(C)(C)C)nn3c2)c1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2ccc3nc(NC(=O)NCCN)nn3c2)c1
Yield: 73.9 %

Procedure:
tert-butyl 2-(3-(6-(5-(N-tert-butylsulfamoyl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)ureido)ethylcarbamate (35 mg) was suspended in HCl (4M in dioxane, 2 mL) and DCM (2 mL) and the reaction mixture stirred overnight at room temperature. After this time the reaction mixture was pippetted slowly onto diethyl ether at −78° C. and maintained at this temperature for 20 minutes. The resultant white solid was filtered, washed with further diethyl ether and dried under vacuum to afford the title compound (21 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:28][C:29]([C:31]2[CH:40]=[C:39]([O:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[O:30])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:28][C:29]([C:31]2[CH:40]=[C:39]([O:41][CH2:42][C:43]([OH:45])=[O:44])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[O:30])[CH2:15][CH2:16][C:17]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccccc3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OCC(=O)O)NC(=O)c2cc(OCC(=O)O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.4 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(((1,1-dimethylethoxy)carbonyl)methoxy)carbonylpropyl]aminocarbonyl-4-((1,1-dimethylethoxy)carbonyl)methoxyquinoline (38 mg, 0.05 mmol) in 1 mL CH2Cl2, was added 2 mL trifluoroacetic acid, then the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil. The oil was diluted in water (5 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×10 mL). The organic layer was evaporated in vacuo to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-((carboxy)methoxycarbonyl)propyl]aminocarbonyl-4-(carboxy)methoxyquinoline as a white solid (30 mg); NMR (DMSO-d6), 1.16 (t, 3), 1.90 (m, 1), 2.10 (m, 1), 2.45 (m, 2), 3.3–3.9 (m, 8), 4.02 (q, 2), 4.52 (q, 2), 5.04 (m, 1), 5.13 (s, 2), 7.46 (s, 1), 7.68 (t, 1), 7.84 (t, 1), 8.08 (d, 1), 8.23 (d, 1), 9.95 (m, 1) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9](=[S:28])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1ccccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1NC(=S)c1ccccc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 150 %

Procedure:
Step 2 A mixture of N-(3-bromo-2-methylphenyl)-2-fluorobenzamide (2.00 g, 6.49 mmol) and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson reagent, 1.575 g, 3.89 mmol) in toluene (25 mL) was heated at reflux. After 3.5 h, the solution was cooled to rt and concentrated to provide a dark yellow solid. This was purified by column chromatography (eluting with a gradient from 95:5 to 90:10 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-2-fluorobenzothioamide as a yellow solid (1.892 g, 90%). 1H NMR (400 MHz, chloroform-d) δ 9.18 (1 H, d, J=7.7 Hz), 8.23 (1 H, td, J=8.0, 1.8 Hz), 7.60 (1 H, d, J=7.9 Hz), 7.45-7.52 (1 H, m), 7.43 (1 H, d, J=7.7 Hz), 7.23-7.30 (1 H, m), 7.11-7.21 (2 H, m), 2.41 (3 H, s). Mass spectrum m/z 324, 326 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].[C:40]1([OH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:46][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(Oc3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Temperature: 110 °C
Yield: 40.7 %

Procedure:
A mixture of 3-[4-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (0.44 mmol, 0.24 g), phenol (0.53 mmol, 0.050 g), K3PO4 (0.88 mmol, 0.19 g), 2-(di-t-butylphosphino)biphenyl (0.066 mmol, 0.020 g), and Pd(OAc)2 (0.044 mmol, 0.010 g) in toluene (7 mL) was degassed under vacuum and backfilled with nitrogen (3×) and heated at 110° C. for 18 h. Additional Pd(OAc)2 (10 mg) and 2-(di-t-butylphosphino)biphenyl (20 mg) were added to ensure complete reaction, and the mixture was heated 5 h. Upon cooling, the mixture was placed directly onto a silica gel column and eluted with 30%-50% EtOAc/hexanes to give 3-(2-(isopropoxycarbonylamino-methyl)-4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid tert-butyl ester (0.11 g).
Reaction SMILES: [P:1]([O:5][CH2:6][C:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][O:16][P:17]([OH:20])([O-:19])=[O:18])[OH:14])[OH:12])[OH:10])=[O:8])([O-:4])([O-:3])=[O:2].[Na+].[Na+].[Na+]>O>[P:1]([O:5][CH2:6][C:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][O:16][P:17]([OH:19])([OH:20])=[O:18])[OH:14])[OH:12])[OH:10])=[O:8])([OH:4])([OH:3])=[O:2]
Reactant: O=C(COP(=O)([O-])[O-])[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(COP(=O)(O)O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Reaction time: 672 h

Procedure:
A 5.0 gram portion of trisodium D-fructose-1,6-diphosphate was dissolved in 10 ml water. The resulting solution was added to 14.1 ml of a 0.67 M aqueous solution of cis-[Pt(NH3)2 (H2O)2 ](NO3)2. The reaction mixture was allowed to stand for 28 days in a 40° C. bath. After that time, the dark blue water-insoluble precipitate which had formed was filtered, washed with water and ethanol, and then dried in vacuum, to yield 0.566 grams of the above-identified complex.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[CH:4]=[N:5]O>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[CH2:4][NH2:5]
Reactant: COc1cc(Cl)cc(Cl)c1C=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc(Cl)cc(Cl)c1CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 2,4-dichloro-6-methoxybenzaldehyde oxime (2.24 mmol) in 3 mL AcOH was cooled to 0° C. and zinc dust (8.53 mmol) was added. The reaction mixture was stirred at RT for 2 h. It was filtered over a pad of celite and washed with EtOAc and MeOH. The filtrate was concentrated and redissolved in water (pH 4 with 2N HCl solution). It was washed once with EtOAc, the ageous phase was basified with 1M NaOH solution, extracted 3 times with EtOAc and DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH2:14][O:15][C:16]2[N:21]=[C:20]([C@H:22]([OH:26])[CH2:23][C:24]#[N:25])[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl>>[NH2:25][CH2:24][CH2:23][C@H:22]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:14][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:21]=1)[OH:26]
Reactant: N#CC[C@@H](O)c1cccc(OCC2CCCCCC2)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(OCC2CCCCCC2)n1

Procedure:
LiAlH4 reduction of (R)-3-(6-(cycloheptylmethoxy)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 1 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 31 as a colorless oil. Yield (0.11 g, 25%); 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=8.0 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 4.56-4.50 (m, 1H), 4.02-3.98 (m, 2H), 2.72-2.60 (m, 2H), 1.92-1.6 (m, 15H); RP-HPLC tR=9.59 min; ESI-MS m/z 279.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.O[C:23]1[CH:31]=[CH:30][C:26]2[CH:27]=[CH:28][O:29][C:25]=2[CH:24]=1.S([O-])(=O)(=O)C>>[O:29]1[C:25]2[CH:24]=[C:23]([O:21][C@@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:31]=[CH:30][C:26]=2[CH:27]=[CH:28]1
Reactant: Oc1ccc2ccoc2c1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(O)c2ccccc2)C1
Agent: CS(=O)(=O)[O-]
Product: c1ccc([C@H](Oc2ccc3ccoc3c2)[C@H]2CNCCO2)cc1

Procedure:
(R)-2-[(S)-(Benzofuran-6-yloxy)-phenyl-methyl]-morpholine was synthesized from 2-(Hydroxy-phenyl-methyl)-morpholine-4-carboxylic acid tert-butyl ester and 6-hydroxybenzofuran according General Procedure C employing the alternate etherification sequence (via the mesylate) and was isolated as an oil. MS (APCI): 310 [M+H]+.