Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:6]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+]>C(O)C>[C:1]([N:6]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:12])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: CCOC(=O)CCN
Reactant: C/C=C/C(=O)N(CCCCC(=O)O)C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C=C/C(=O)N(CCCCC(=O)NCCC(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-crotonoyl-5-benzhydrylaminovaleric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-(N-crotonoyl-5-benzhydrylaminopentanoyl)-3-aminopropionic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29].CC#N>CN(C=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:28](=[O:29])[CH2:27][Cl:26])[CH2:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCN2
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a stirring solution of 2,3-dihydro-1H-indole-5-sulfonic acid thiazol-2-ylamide (2.35 g, 8.36 mmol) in DMF (10 mL), at −75° C., was added triethylamine (1.16 mL, 8.36 mmol) followed by chloroacetyl chloride (1.88 g, 16.7 mmol). The mixture was stirred at −75° C. for 1 h. The reaction showed product formation by LC/MS (10-99% CH3CN). After quenching with MeOH and allowing the mixture to warm to room temperature, the solvents were removed in vacuo. The mixture was purified via column chromatography (2% MeOH in CH2Cl2) to obtain the desired amide (1.95 g, 5.9 mmol, 70% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=359.3; tR=2.46 min.
Reaction SMILES: C[N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)C=CC=1)[CH3:3].[CH:14]([O:17]C1C=CC(CC(O)=O)=CC=1)([CH3:16])[CH3:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1>O1CCCC1>[N:2]([CH2:4][C:13]1[CH:12]=[CH:11][C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=[C:3]=[O:35]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(C)c1cccc2ccccc12
Reactant: CC(C)Oc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(CN=C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
1,8-Bis(dimethylaminonaphtalene (3.19 g, 14.9 mmol) was added to a solution of 4-(isopropoxy)phenyl acetic acid (2.89 g, 14.9 mmol) in dry tetrahydrofuran (18 mL) at rt under argon atmosphere. After 25 minutes stirring at rt diphenylphosphoryl azide (4.10 g, 14.9 mmol) was added dropwise and the mixture refluxed for 6 hours. It was allowed to cool to rt and then stored at −20° C. overnight to precipitate out the ammonium phosphate salt. A mixture of diethyl ether and ethyl acetate (1:1 v/v, 25 mL) was added to the cold reaction mixture. The precipitate was filtered from the reaction mixture and washed with diethyl ether: ethyl acetate (1:1 v/v, 20 mL). The filtrate was evaporated to dryness giving 1-isocyanatomethyl-4-isopropoxybenzene as an oil (3.2 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Br[CH:11]([CH2:14][CH2:15]Cl)[CH:12]=[O:13]>O>[CH:12]([C:11]1([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:15][CH2:14]1)=[O:13]
Reactant: CC(C)(C)S
Reactant: O=CC(Br)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)SC1(C=O)CC1
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen and while cooling with ice, 112 ml of tert-butyl mercaptan are added dropwise over 10 minutes to a solution, cooled to 5° C., of 80 g of sodium hydroxide in 750 ml of water. Then 50 ml of methanol are added. After 1 hour, 151 g of 2-bromo-4-chlorobutanal (89.5%) are added dropwise over 15 minutes with efficient stirring and cooling, whereupon the temperature of the reaction mixture rises from 5° to 20° C. After 30 minutes, the mixture is extracted 4 times with diethyl ether. The combined organic phases are washed twice with a saturated solution of sodium chloride and dried over magnesium sulfate. The residue obtained after concentrating the residue on a rotary evaporator is fractionated over a 30 cm packed column, affording 89 g of 1-formyl-1-tert-butylthiocyclopropane in 89% purity. Boiling point: 112°-114° C./8 400 Pa.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH:17]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)(=[O:7])=[O:6])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCOCC1.O>[CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH:17]1[N:18]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:6])=[O:7])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-N-(8-{[(1R)-1-phenylethyl]amino}-1,4-dioxaspiro[4.4]nonan-7-yl)propane-2-sulfonamide (274 mg, 0.72 mmol) and sodium carbonate (114 mg, 1.074 mmol) in 1,4-dioxane (2 ml) and water (0.4 ml) at 0° C. was added drop wise benzyl chloroformate (CAS number 501-53-1; 0.13 ml, 0.90 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-70% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(#N)C>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Solvent: CCOCC
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
250 mg. (1.06 mmol) 3-(1,6-dihydro-6-oxo-9H-purin-9-yl) propionic acid, ethyl ester (AIT-0027) was added to a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then, 604 mg (3.17 mmol) 4-amino-1-benzyl-piperidine and 1 ml acetonitrile were added and the solution was brought to reflux. Reflux was continued for 17 hours. Aacetonitrile was evaporated and the mixture was heated at 120° C. for eight hours to yield a dark viscous oil. The oil was treated with ether while stirring. The solution was filtered and the orangebrown solid was washed with additional ether. Upon drying, 385 mg of a brown solid was obtained. The solid was stirred in acetone, filtered, washed with acetone and then with ether. This yielded 200 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(1-benzylpiperidin-4-yl)propanamide (AIT-0033) as a tan solid. Analysis by HPLC indicated that the product was 65% pure.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[CH:38][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:28]4=[O:37])[CH2:23][CH2:22]3)=[O:20])=[C:17]([O:40][CH3:41])[CH:16]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH:3]([S:4]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[CH:38][C:18]([C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:28]4=[O:37])[CH2:25][CH2:26]3)=[O:20])=[C:17]([O:40][CH3:41])[CH:16]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:5])=[CH2:2]
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: O=S(=O)(Cl)CCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(Oc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OC)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL flask containing 3 mL of methylene chloride was added 2-chloro-1-ethanesulfonyl chloride (0.046 mL, 0.44 mmol) and the solution was cooled to 0° C. under N2. To a 10 mL addition funnel containing 8 mL of methylene chloride was added 1-(1-(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (200 mg, 0.4 mmol) from Example 190 and DIEA (0.35 mL, 2.0 mmol). This solution was added slowly over 15 min to the cold, stirred solution of sulfonyl chloride. The reaction mixture was stirred at 0° C. for 30 min and then at ambient temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue purified by pressurized silica gel column chromatography using 95:5 CH2Cl2 :MeOH as eluant. The product-containing fractions were combined and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12](I)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])#[CH:17].CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(I)ccn1
Reactant: C#Cc1ccccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1C#Cc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of (4-iodo-pyridin-2-yl)-carbamic acid tert-butyl ester (250.0 mg, 0.781 mmol), 1-ethynyl-2-methoxy-benzene (93.8 mg, 0.710 mmol), CuI (13 mg, 0.071 mmol), Pd(PPh3)2Cl2 (25 mg, 0.036 mmol), and Et3N (9 mL) in dry DMF (3 mL) is stirred at room temperature for 19 hours. The reaction is diluted with ethyl acetate (20 mL) and quenched with saturated aqueous NH4Cl (10 mL). The organic layer is washed with an additional portion of saturated aqueous NH4Cl (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified on SiO2 (0-30% ethyl acetate in heptanes, gradient) to give the product.
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21].ClCl.C(O)C>CCCCCC.C(OCC)(=O)C>[C:20]([NH:25][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])([CH2:23][CH3:24])([CH3:22])[CH3:21]
Reactant: CCC(C)(C)N
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Agent: ClCl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(C)(C)Nc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and tert-amylamine (4 ml, 0.034 mol) in enough CH2 Cl2 to form a solution (a small amount of dry ethanol was required) was stirred at room temperature for two days. During this time, a precipitate forms. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated to a solid on a rotary evaporator. The solid is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-(tert-amylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.253 g (0.00085 mol, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:32]\[OH:33])=[C:4]([CH3:30])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam, MS (ESI+): m/z=459.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:6]=1.[Br:17]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[N:5][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nnc(-c2ccccc2C(F)(F)F)s1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nnc(CBr)s1
Temperature: 25 °C

Procedure:
172 mg (0.70 mmol) of the compound from Example 72A together with 251 mg (1.41 mmol) of N-bromosuccinimide and 12 mg (0.07 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride were heated under reflux for 8 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 33 mg (15% of theory) of the target compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:13][C@@H:10]2[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:35](=O)([O-])[O-:36].[K+].[K+].S(=O)(=O)(O)O>CO>[OH:12][CH2:11][C:10]1([O:13][C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:35][OH:36]
Reactant: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: OCC1(CO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 1.18 g portion of 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose prepared in accordance with Examples 1-3 was dissolved in 8.5 ml of methanol, treated with 5.11 ml of 37% formalin and 480 mg of potassium carbonate and the mixture immersed in an 85° C. bath. After 4 hours the mixture was cooled, neutralized with 3.5 ml of 10% sulfuric acid and the volatiles removed. The residue was extracted with chloroform, giving 0.86 g of the desired compound after chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[C:18]=2[CH2:27][CH2:28][CH3:29])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:31](=O)([O-])[O-].[Cs+].[Cs+].IC>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([O:26][CH3:31])[C:18]=2[CH2:27][CH2:28][CH3:29])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCCc1c(OCCCOc2cccnc2CCC(=O)OC)ccc(C(C)=O)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: CCCc1c(OCCCOc2cccnc2CCC(=O)OC)ccc(C(C)=O)c1OC
Yield: 91.9 %

Procedure:
Under the conditions of example 2 A, 600 mg of 3-{3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxy]-2-pyridyl}-propionic acid methyl ester in the presence of 940 mg of cesium carbonate instead of potassium carbonate is reacted with 205 mg of iodomethane, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 570 mg of 3-{3-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[C:4]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][NH:17]2)[CH:3]=1.CCN(CC)CC.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34]([N:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[O:6][CH2:7][C:8]1[O:12][N:11]=[C:10]([OH:13])[CH:9]=1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cc(COc2ccc(Cl)cc2C2NCCc3ccccc32)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1OCc1cc(O)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of (±)-5-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxymethyl]-isoxazol-3-ol (49 mg, 0.138 mmol, 1.0 eq.) and NEt3 (58 μL, 0.414 mmol, 3.0 eq.) in DCM (3.8 mL), benzyl chloroformate (23 μL, 0.152 mmol, 1.1 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (3.8 mL). The layers were separated. The aq. phase was extracted with DCM (3×). The comb. org. phases were concentrated in vacuo. The residue, redissolved in DMF, was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=3)[CH:27]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2c(ccn2Cc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
This compound was prepared from methyl-5-indole carboxylate and 3-(quinolin-2-ylmethoxy)benzyl chloride (Example 5a) by the method described in Example 1b, part i.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([C@@H:45]2[CH2:47][C@H:46]2[C:48](Cl)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:48]([C@@H:46]3[CH2:47][C@H:45]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)[C@@H]1C[C@H]1c1ccccc1)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the mixture cooled to 0° C. Added to this was (1R,2R)-2-phenylcyclopropanecarbonyl chloride (10 μl, 0.07 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% CF3CO2H, Sunfire 19×100 mm, C18, 5 μm). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate isolated by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-((1R,2R)-2-phenylcyclopropanecarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (5.5 mg, 39% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 6.61-7.66 (9H, m), 4.70-4.87 (1H, m), 4.09-4.63 (2H, m), 3.40-4.02 (3H, m), 2.24-2.49 (1H, m), 2.06-2.23 (1H, m), 1.80-1.96 (1H, m), 1.45-1.76 (1H, m), 1.20-1.45 (10H, m), 1.11-1.19 (3H, m), 0.86-1.03 (8H, m). 19F NMR (500 MHz, CD3OD) δ ppm −115.29, −115.86. LCMS (M+H) calcd for C12H42FN2O4: 573.31. found: 573.08.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(CC)CC>C(Cl)Cl>[O:12]=[C:10]([N:29]1[CH2:28][CH2:27][CH2:26][CH2:24]1)[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a mixture of (R)-2-(tert-butoxycarbonylamino)butanoic acid (1.5 g, 7.38 mmol), HATU (3.37 g, 8.86 mmol) and pyrrolidine (1.303 mL, 14.76 mmol) in DCM (50 mL) was added Et3N (2.057 mL, 14.76 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.6 g, 85%). 1H NMR (500 MHz, CDCl3) δ 0.88-1.04 (m, 3 H) 1.38-1.48 (m, 9 H) 1.52-1.64 (m, 1 H) 1.69-1.79 (m, 1 H) 1.82-1.92 (m, 2 H) 1.92-2.02 (m, 2 H) 3.36-3.47 (m, 2 H) 3.53 (dt, J=12.08, 7.14 Hz, 1 H) 3.65 (dt, J=10.01, 6.47 Hz, 1 H) 4.30-4.43 (m, 1 H) 5.37 (d, J=8.30 Hz, 1 H).