Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18](S(C)=O)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:30]1([C:36]2[N:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>ClC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:33]3[CH2:34][CH2:35][N:30]([C:36]4[N:37]=[CH:38][CH:39]=[CH:40][N:41]=4)[CH2:31][CH2:32]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CN(C)c1cc(Nc2cccc(OCc3ccccc3)c2)nc(S(C)=O)n1
Agent: Cl
Solvent: Clc1ccccc1
Product: CN(C)c1cc(Nc2cccc(OCc3ccccc3)c2)nc(N2CCN(c3ncccn3)CC2)n1
Yield: 42.5 %

Procedure:
A mixture of N4-[3-(benzyloxy)phenyl]-N6,N6-dimethyl-2-(methylsulfinyl)-4,6-pyrimidinediamine (30 mg, 0.078 mmol) and 2-(1-piperazinyl)pyrimidine dihydrochloride (74 mg, 0.312 mmol) in chlorobenzene (2 mL) was heated at reflux for 15 hours. The crude product was purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (7:3)], giving the desired product (16 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:24](CC4C=CC=CC=4)[N:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[F:32])([CH3:12])[N:3]=1.[ClH:33]>CO.O1CCOCC1.[Pd]>[ClH:33].[NH:24]1[C:20]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:32])=[C:13]([C@@:4]3([CH3:12])[N:3]=[C:2]([NH2:1])[N:7]([CH3:8])[C:6](=[O:9])[C:5]3([CH3:10])[CH3:11])[CH:18]=2)=[CH:21][CH:22]=[N:23]1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccnn3Cc3ccccc3)ccc2F)N=C1N
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccn[nH]3)ccc2F)N=C1N
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-6-(5-(1-benzyl-1H-pyrazol-5-ylamino)-2-fluorophenyl)-3,5,5,6-tetramethyl-5,6-dihydropyrimidin-4(3H)-one (example 107, 0.02 mmole) in methanol (1 ml) was added a solution of aqueous 4M HCl in 1,4-dioxane (0.25 ml) and Pd/C (10%, 3 mg) under argon. The reaction mixture was hydrogenated at 1 atm H2 for 2 h, filtered over Decalite and the residue was washed with methanol. The filtrate was concentrated in vacuo and the residue purified by flash chromatography on NH2-silica using a gradient of dichloromethane/methanol to yield the title compound as a colorless waxy solid. MS (ESI): m/z=345.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:48][C:49]1[CH:65]=[C:64]([C:66](=[NH:69])[NH:67]O)[CH:63]=[C:62]([CH3:70])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>CN(C=O)C>[Cl:48][C:49]1[CH:65]=[C:64]([C:66]2[N:67]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:69]=2)[CH:63]=[C:62]([CH3:70])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OCCCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3cc(C)c(OCCCC(=O)OC(C)(C)C)c(Cl)c3)no2)cc(C2CCCC2)n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
A mixture of 2-cyclopentyl-6-methoxy-isonicotinic acid (33 mg, 0.149 mmol), TBTU (50 mg, 0.156 mmol) and DIPEA (62 mg, 0.479 mmol) in DMF (2 mL) is stirred at rt for 15 min before tert-butyl 4-(2-chloro-4-(N-hydroxycarbamimidoyl)-6-methylphenoxy)butanoate (51 mg, 0.149 mmol) is added. The mixture is stirred at rt for 1 h before another portion of TBTU (50 mg, 0.156 mmol) is added. Stirring is continued at rt for 2 h. The mixture is heated to 110° C. and stirring is continued for another hour. The mixture is concentrated and the crude product is purified by prep. HPLC to give tert-butyl 4-(2-chloro-4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methylphenoxy)butanoate (33 mg) as a colourless glass; LC-MS: tR=1.28 min, [M+H]+=528.37.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=[CH:8]2)(=O)C.CCN(C(C)C)C(C)C.ClC(OCC)=O.[NH2:33][C:34]1[CH:38]=[C:37]([CH3:39])[O:36][N:35]=1>C1COCC1.CCOC(C)=O.O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([NH:33][C:34]1[CH:38]=[C:37]([CH3:39])[O:36][N:35]=1)=[O:17])=[CH:10][CH:9]=[CH:8]2
Reactant: CC(=O)Oc1ccc2c(C(=O)O)cccc2c1
Reactant: Cc1cc(N)no1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)c2cccc3cc(O)ccc23)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Acetoxy-1-naphthoic acid (200 mg, from Example 1) was mixed with DIPEA (1.2 eq) in THF and stirred at 0° C. for 10 minutes, to the reaction was added ethyl chloroformate (1 eq) slowly and further stirred for 1.5 hours from 0° C. to RT. To the reaction was added DIPEA (1.2 eq) and 3-amino-5-methylisoxazole (1.2 eq), the reaction was stirred at RT for 12 hours and mixed with EtOAc/H2O, further extracted with EtOAc and dried. The solution was evaporated and mixed with 15% KOH (2 ml) in MeOH (10 ml) further stirred at RT for 30 minutes. The solvent was evaporated and the residue was adjusted to weak acidic with 2N HCl, the solid was filtered and washed with water twice and cold MeOH to give 6-Hydroxy-N-(5-methylisoxazol-3-yl)-1-naphthamide (90 mg).
Reaction SMILES: [Br-].[CH2:2]([N+:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH:7]=1)[CH2:3][CH2:4][CH3:5].C1(CCN2CCCC(C(C)=O)=C2)C=CC=CC=1>>[CH2:2]([N:6]1[CH2:11][CH2:10][CH2:9][C:8]([C:12]([CH2:13][CH2:14][CH3:15])=[O:16])=[CH:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1cccc(C(=O)CCC)c1
Agent: CC(=O)C1=CN(CCc2ccccc2)CCC1
Agent: [Br-]
Product: CCCCN1C=C(C(=O)CCC)CCC1

Procedure:
1-Butyl-3-butyryl pyridinium bromide was hydrogenated according to the procedure described in Part (b) of Example 6 to give propyl 1-butyl-1-4,5,6-tetrahydro-3-pyridyl ketone (13). The product was distilled as a pale yellow oil (b.pt. 120-124°C./0.02 mm Hg).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])#[N:5].O>O1CCCC1>[C:4]([C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH3:1])#[N:5]
Reactant: N#Cc1ccccc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccccc1C#N
Temperature: 25 °C

Procedure:
A 1M solution of methylmagnesium bromide in tetrahydrofuran (12 ml, 12 mmol) was dropwise and portionwise added to a solution of 2-cyanobenzaldehyde (1.31 g, 10.0 mmol) dissolved in dried tetrahydrofuran (25 ml), followed by stirring at room temperature for one night. After the reaction, water was added to the reaction mixture followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the solution was concentrated under reduced pressure to give 1-(2-cyanophenyl)ethanol (1.47 g, quantitative).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC2CCCCC2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
A mixture of 4-cyclohexyloxy-benzaldehyde (2.84 g, 13.9 mmol) described in Manufacturing Example 79-1-1, nitromethane (3.74 mL, 69.5 mmol), ammonium acetate (2.14 g, 27.8 mmol) and acetic acid (30 mL) was stirred for 14 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.3 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1)(=[O:28])=[O:27]
Reactant: COc1cc2ccc(CCO)cc2cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ccc(CCOS(C)(=O)=O)cc2cc1OC
Temperature: 3 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 5.03 g (0.0216 mole) of 2-(2-hydroxyethyl)-6,7dimethoxynaphthalene in 75 mL of methylene chloride, cooled in an ice bath, was added 6 mL (0.043 mole) of triethylamine followed by 2.2 mL (0.028 mole) of methanesulfonyl chloride. The reaction mixture was stirred at 3° C. for 1 hour and then was washed with 1N hydrochloric acid, 5% sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2-(2-methanesulfonyloxyethyl)-6,7-dimethoxynaphthalene, which was used without purification. A mixture of this mesylate, 5.5 g (0.019 mole) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 0.7 mL of TDA-1 and 5.4 g (0.039 mole) of potassium carbonate in 180 mL of toluene was stirred at reflux for 18 hours. The reaction mixture was washed with water, dried and concentrated under reduced pressure to a solid which was recrystallized from methylene chloride-methanol-water, to give 8.6g (89% yield), mp 112°-113° C., of 2-hydroxy-4-[2-(6,7-dimethoxy-2-naphthalenyl)ethoxy]-3-propylbenzoic acid phenylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][N+:4]=1[O-].[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(N)ccn1
Temperature: 100 °C

Procedure:
A mixture of 6.3 g of 2-methoxy-4-nitropyridine N-oxide and 12.6 g of iron powder in 150 ml of acetic acid is heated for 1 hour at 100° C. After cooling, sodium hydroxide is added, the mixture is then filtered and the material on the filter is washed with water. The aqueous phase is extracted with ethyl ether. After drying and concentration, 3.6 g of an oil are recovered which crystallizes to a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].C(N=C=[Se:41])C1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[Se:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Se]=C=NCc1ccccc1
Reactant: O=CNCCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [Se]=C=NCCc1ccccc1
Yield: 95 %

Procedure:
(AS3.091) A mixture of phenylethylformamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2b as an oil. 1H NMR (CDCl3) δ 3.03 (t, 2H, J=6.9 Hz), 3.81 (t, 2H, J=6.9 Hz) 7.20-7.38 (m, 5H); HRMS (EI) calcd for C9H9NSe, 210.9895. found, 210.9892.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cncc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 5-methylpyridin-3-amine (0.5 g, 4.62 mmol) in CH2Cl2 (50 ml) were added triethylamine (0.64 mL, 4.62 mmol) and methyl 2-(chlorosulfonyl)benzoate (1.08 g, 4.62 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (0-8% MeOH/CH2Cl2) to give the title compound (0.476 g, 34%). 1H NMR (400 MHz, DMSO-D6) δ ppm 10.25-10.62 (m, 1H) 8.6 (s, 2H) 7.81-7.93 (m, 1H) 7.64-7.76 (m, 2H) 7.54-7.64 (m, 1H) 7.28 (s, 1H) 3.80 (s, 3H) 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([Br:5])([Br:4])[Br:3].C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].O>C(OCC)C>[Br:3][C:2]([Br:5])([Br:4])[CH2:1][O:6][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: OCC(Br)(Br)Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)OCC(Br)(Br)Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
A first solution comprising tribromoethanol (50 g, 177 mmol) and triethylamine (19.73 g, 195 mmol) dissolved in 70 g of diethylether was prepared. A second solution comprising methacryloyl chloride (20.39 g, 195 mmol) dissolved in 70 g of diethylether was added dropwise to the first solution followed by stirring for four hours at room temperature. The resulting solution was then added to water, and the organic phase was extracted. The organic phase was distilled to yield 32.85 g of TBEMA (52.9% yield).
Reaction SMILES: NC1C=CC(C(OC)=O)=CC=1C.[C:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[CH:19]2)([OH:15])=[O:14]>>[C:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:19]2)([OH:15])=[O:14]
Reactant: C=C(C)CCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: COC(=O)c1ccc(N)c(C)c1
Product: CC(C)CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
Refer to Example 1 using methyl 4-amino-3-methyl-benzoate instead of o-toluidine, or refer to Example 32b) using 5-carboxy-2-(2-methyl-1-buten-4-yl)indole as the starting material.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:16]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:15]2[CH:16]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=2[CH3:21])(=[O:18])=[O:19])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Yield: 59.3 %

Procedure:
3-Amino-5-bromo-2-chloropyridine (797 mg) in dry pyridine (10 ml) was treated with 5-fluoro-2-methylbenzenesulfonyl chloride (962 mg) then stirred at RT over the weekend. The reaction was purified by prep-HPLC. Desired fractions were concentrated under reduced pressure, diluted with saturated sodium bicarbonate (aq) and brine and extracted into DCM. The solvent was dried over magnesium sulfate, filtered then evaporated to give title compound (865 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[C:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][C:18]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:16])=[C:13]([C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[C:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:16])=[C:13]([C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:47])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2c(OCc3ccccc3)cccc2C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 68.4 %

Procedure:
A solution of 0.428 g (0.582 mmol) of 1,1-dimethylethyl 4-(6-benzyloxy-2-(benzyloxycarbonyl)benzoyl)-3,5-dibenzyloxybenzoate in 5 mL of distilled quinoline was heated at 200° C. under an atmosphere of nitrogen for 3 h. The mixture was then cooled, poured onto 75 mL of ether and washed three times with 2N HCl and once with brine. The organic extracts were dried over magnesium sulfate and evaporated to give 0.42 g of the crude product, which was recrystallized from isopropanol to give 0.270 g (68%) of the title compound as a tan solid, mp 151°-156° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1c[nH]c2ccccc12
Yield: 95 %

Procedure:
To a mixture of 3-indolepropionic acid (4.00 g, 1 eq) in ethanol (70 ml), 1 ml of sulphuric acid is added dropwise and the mixture is first refluxed overnight and then evaporated to dryness. The resulting crude residue is dissolved in ethyl acetate and the organic solution is washed with 5% aqueous sodium bicarbonate, water, dried over MgSO4, filtered and finally evaporated to dryness, to afford the title compound as a yellow solid (4.30 g, 95% yield), which is used as such for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].[O:21]=O>CN(C=O)C.O.[Pd](Cl)Cl.[Cu]Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12](=[O:21])[CH3:13])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:4]
Reactant: CC=CCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CC(CCC(C)=O)CN1C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
To a solution of 4-but-2-enyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (149 mg, 0.42 mmol, 1 equiv) in DMF (1.4 mL) and water (0.2 mL) were added palladium(II)chloride (7.4 mg, 0.042 mmol, 0.1 equiv) and copper(I) chloride (41.1 mg, 0.42 mmol, 1 equiv). The mixture was stirred at 50° C. overnight with oxygen bubbling into the mixture. The mixture was filtered and the filtrate was concentrated under high vacuum. The residue was diluted with ethyl acetate, washed with water (1×), brine (1×), dried and concentrated. The residue was purified by preparative TLC to give 4-(3-oxo-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (110 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[NH:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:16]I>>[CH3:16][N:4]1[CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)[CH:7]=[C:2]([CH3:1])[C:3]1=[O:15]
Reactant: Cc1cc(C2CCC(=O)CC2)c[nH]c1=O
Reactant: CI
Product: Cc1cc(C2CCC(=O)CC2)cn(C)c1=O

Procedure:
The title compound was prepared as a white solid from the methylation of 3-methyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in Example 44, Step C) with MeI using the procedure described in Step B of Example 38.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:40])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]3[CH:39]=[CH:38][C:29]4[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=4[CH:27]=3)[CH:19]=2)[C:5]([CH3:17])=[C:6]([Cl:16])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:40])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]3[CH:39]=[CH:38][C:29]4[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=4[CH:27]=3)[CH:19]=2)[C:5]([CH3:17])=[C:6]([Cl:16])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of methyl [(3S)-6-({3′,5′-dichloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.617 g, 1.02 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.520 g, yield 86%) as colorless crystals.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([OH:22])[C@H:20]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:19]([CH2:32][OH:33])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H]1(O[C@H]2[C@H](O)[C@@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)O[C@H](OCCN)[C@H]2O)O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O.[C:71](Cl)([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:9][C@H:10]1[C@@H:21]([OH:22])[C@H:20]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:19]([CH2:32][O:33][C:71]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[O:18][C@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Solvent: c1ccncc1
Product: [N-]=[N+]=NCCO[C@@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](O)[C@@H]1OC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
In a 250 ml round bottom flask, 2-azidoethyl 2,4-di-O-benzoyl-α-D-mannopyranoside (1.0 g, 2.186 mmol; See WO 2010/088294 A1, incorporated herein by reference) was dissolved in pyridine (50 mL). To the above solution was added DMAP (13 mg, 0.109 mmol) followed by trityl chloride (762 mg, 2.73 mmol). After stirring at 80° C. for 18 hr, the reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (40 g), eluting with 0-50% EtOAc in hexanes to give the title compound. UPLC Method C: m/e=722.2955, [M+Na]; Rt=4.50. 1H NMR (CDCl3) δ 7.0-8.3 (m, 25H), 5.8 (t, 1H), 5.5(m, 1H), 5.2 (s, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 4.0 (m, 1H), 3.5 (m, 1H), 3.4 (m, 2H), 3.2 (dd, 1H), 2.7 (d, 1H).