Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][O:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([Cl:25])=[O:24])[CH2:18][C:17]2=[O:26]>C(N(CC)CC)C>[ClH:25].[CH3:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:24])[CH2:18][C:17]2=[O:26]
Reactant: C1CCN(CC2COCCN2)C1
Reactant: Cc1ccc2c(c1)C(=O)CC2C(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(=O)CC2C(=O)N1CCOCC1CN1CCCC1
Product: Cl
Yield: 15.3 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.89 g of 3-(pyrrolidin-1-ylmethyl)morpholine, 2.2 ml of triethylamine and 0.83 g of 5-methyl-3-oxoindan-1-carbonyl chloride, to afford 0.23 g of the title compound, melting at 225°-230° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH2:11][CH2:10]1)(=O)[CH3:7].[C:24]([C:26]1[C:32]([O:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)=[C:31]([O:38][CH3:39])[C:30]([O:40][CH3:41])=[CH:29][C:27]=1[NH2:28])#[N:25].[OH-].[Na+]>ClCCl.O>[NH3:9].[CH:34]1([O:33][C:32]2[C:31]([O:38][CH3:39])=[C:30]([O:40][CH3:41])[CH:29]=[C:27]([N:28]=[C:6]([N:9]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH2:11][CH2:10]3)[CH3:7])[C:26]=2[C:24]#[N:25])[CH2:35][CH2:36][CH2:37]1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OC2CCC2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OC2CCC2)c1OC
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Phosphorous oxychloride (210 ΠI, 0.0022 mol) was added to a solution of 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane (1.02 g, 0.0040 mol) in dichloromethane (10 ml) and the solution stirred at room temperature for 1 hour. 2-Cyano-3-cyclobutyloxy-4,5-dimethoxyaniline (500 mg, 0.002 mol) was then added and the reaction stirred at reflux under a nitrogen atmosphere for 18 hours. On cooling, water (30 ml) and aqueous sodium hydroxide solution were added and the mixture extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with dichloromethane:methanol:0.880 aqueous ammonia solution (96:3.5:0.5 v/v) to give the subtitle compound as a gum (950 mg, 97%). Rf 0.62 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 486 (MH)+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(NC1C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1)=O.C1CCN2C(=NCCC2)CC1>CC#N>[N+:27](=[C:9](/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([O:12][CH3:13])=[O:11])=[N-:28]
Reactant: COC(=O)C/C=C/c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(/C=C/c1ccccc1)=[N+]=[N-]
Temperature: 25 °C
Yield: 68 %

Procedure:
To a stirred solution of (E)-methyl 4-phenylbut-3-enoate (S32) and p-ABSA (see reference above for preparation of p-ABSA) in CH3CN cooled to 0° C., was added DBU. The reaction mixture was allowed to warm to room temperature over 7 h then quenched with saturated ammonium chloride (NH4Cl). The aqueous layer was extracted with diethyl ether three times and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was triturated with a solution of pentane:diethyl ether (1:1). The solid was filtered off and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, pentane:diethyl ether (15:1)) to give the title compound (S33) in 68% yield as a dark red solid, which was stored neat at −10° C. until ready for use.
Reaction SMILES: O.O[N:3]1[C:7]2C=CC=[CH:11][C:6]=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]1([C:30]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][C:37]3[NH:36][N:35]=[C:34]([C:39](O)=[O:40])[C:33]=3[CH:32]=[CH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCC1>ClCCl.C(N(CC)CC)C>[N:3]1([C:39]([C:34]2[C:33]3[CH:32]=[CH:31][C:30]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:38][C:37]=3[NH:36][N:35]=2)=[O:40])[CH2:11][CH2:6][CH2:7]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)N1CCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
0.256 g of 1-hydroxybenzotriazole hydrate and 0.364 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to 0.5 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in suspension in 100 cm3 of dichloromethane. After stirring for 30 minutes at a temperature in the region of 20° C., a solution of 0.114 g of azetidine and 0.303 g of triethylamine in 10 cm3 of dichloromethane is added to the reaction mixture. After stirring at a temperature in the region of 20° C. for about 20 hours, the reaction mixture is diluted with 300 cm3 of dichloromethane and then washed with 3 times 100 cm3 of water. The resulting organic phase is dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)] to give 0.37 g of azetidin-1-yl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone, in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=1)#[N:2].[C:20](Cl)(=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>N1C=CC=CC=1>[C:1]([CH2:3][CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[N:17]=1)[C:20](=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])#[N:2]
Reactant: Cc1cc(C)nc(NCCCCCNCCC#N)n1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)N(CCC#N)CCCCCNc1nc(C)cc(C)n1

Procedure:
Crude XIII was dissolved in dry pyridine to which 1 eq of tetradecanoyl chloride was added with stirring. The run was followed by tlc and excess acid chloride was added to drive the reaction to completion. Ice was then added to quench the reaction followed by the addition of CHCl3. The mixture was first extracted with 10% NaHCO3 and then with 1M HOAc to remove the bulk of the pyridine. The remaining CHCl3 phase was evaporated to yield the crude product which was purified by chromatography on a 100 g silica gel (Brinkman 50-200μ) column developed with 30% acetone/chloroform. The product (1 g) was collected after only 150 ml of eluant had passed through the column and was only partially purified.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[CH:31]([NH:34][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:2])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reactant: CC(C)N
Product: CC(C)NC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid isopropylamide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and isopropylamine in an analogous manner to example 12. MS calcd. for C26H36N3O3[(M+H)+] 438.0, obsd. 437.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=O)[NH:25][N:24]=[N:23]2)=[CH:18][CH:17]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C(=O)N(C2C=CC(F)=CC=2)N=N1)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:26]2[N:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[N:23]=[N:24][N:25]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(F)cc1
Agent: C[C@@H](n1nnn(-c2ccc(F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nnnn1-c1ccc(F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 9.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.43 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.03 g of 1-(4-fluorophenyl)-5(1H,4H)-tetrazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-fluorophenyl)-5(1H,4H)-tetrazolone (1.22 g) and 205 mg of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-fluorophenyl)-1H-tetrazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([Cl:24])=[C:20]([O:22][CH3:23])[CH:21]=2)[N:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([Cl:24])=[C:20]([O:22][CH3:23])[CH:21]=2)[N:3]=1
Reactant: COc1cc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)(C)O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-chloro-5-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (85 mg, 0.220 mmol) in 2 mL of THF at 0° C. was treated with methylmagnesium bromide (0.73 mL of 3.0 M solution in ether, 2.20 mmol) and stirred at this temperature for 15 min. It was quenched with ice cold saturated NH4C1 solution and extracted twice with EtOAc. The combined organic solution was concentrated and the residue was purified on a silica gel column and eluted with 50 to 100% EtOAc in DCM to give the title compound (23 mg, 26% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (br., 1H), 8.97 (d, J=2.6 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 5.21 (s, 1H), 3.94 (s, 3H), 2.47 (s, 3H), 1.49 (s, 6H). m/z (ESI, positive ion) 402.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])C(O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:35])=[CH:4][CH:3]=1
Reactant: O=C(O)C(=Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
Part B; 3-(4-Bromophenyl)-2-(2,4-dichlorophenyl)acrylic acid (26.55 gram, 71 mmol) is dissolved in anhydrous toluene (130 mL) and the resulting solution is cooled to 0° C. Triethylamine (7.40 gram, 73 mmol) and diphenylphosphoryl azide (19.8 gram, 72 mmol) are successively added and the resulting mixture Is stirred at 0° C. for 20 minutes and 150 minutes at room temperature. The reaction mixture is poured into water and extracted three times with diethyl ether. The collected organic layers are dried over MgSO4 and the diethyl ether Is removed in vacuo. The resulting toluene layer is slowly added to refluxing toluene (150 mL). t-Butanol is added after 90 minutes and heating at reflux temperature is continued for 1 hour, followed by slow addition of concentrated hydrochloric acid (5 mL). After stirring the resulting solution overnight at 90° C. it is allowed to attain room temperature, washed twice with water, dried over MgSO4, filtered and evaporated in vacuo to give a yellow oil. This oil is crystallised from n-hexane to give 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (14.72 gram, 60% yield). Melting point: 69-70° C.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36]>CN(C)C=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][N:26]3[C:27](=[O:36])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]3=[O:35])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc3ccccc23)CC1
Temperature: 90 °C

Procedure:
A suspension of 1.17 g (5.52 mmol) of 1-(1-naphthyl)piperazine (Tetrahedron Letters, 1998, 39(15), 2219–2222), 0.99 g (7.15 mol) of potassium carbonate and 1.68 g (6.62 mmol) of 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione in 15 ml of N,N-dimethylformamide is heated at 90° C. for 2 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Cl[CH2:9][C:10](=O)[CH3:11].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>O>[CH3:11][C:10]1[CH:7]=[C:2]2[N:1]([CH:9]=1)[CH:6]=[CH:5][CH:4]=[CH:3]2
Reactant: CC(=O)CCl
Reactant: Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccccn2c1
Temperature: 95 °C
Yield: 79.4 %

Procedure:
A mixture of α-picoline (5 g, 53.8 mmol) and chloroacetone (5 g, 53.8 mmol) was heated at 90-100° C. for 4 h. The reaction mixture was then poured into a chloroform/water mixture (50:50 mL) and subsequently extracted. The aqueous phase was treated with 0.6 g of sodium bicarbonate and then extracted with diethyl ether (3×30 mL) to remove the residual α-picoline. A further 8.1 g (96.4 mmol) of sodium bicarbonate were added to the aqueous phase, and the mixture was concentrated to give a mixture of white precipitate and water. Extracting the mixture with diethyl ether gave 5.6 g of 2-methylindolizine 1 in the form of white crystals; m.p.: 57-58° C. 1H NMR (CDCl3): δ 7.77-7.74 (m, 1H), 7.23 (d, J=8.9 Hz, 1H), 7.06 (s, 1H), 6.58-6.53 (m, 1H), 6.36-6.31 (m, 1H), 6.21 (s, 1H), 2.31 (s, 3H), 13C NMR (CDCl3): δ 132.8, 124.8, 124.6, 118.2, 116.5, 111.1, 109.4, 99.7, 12.4.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[ClH:18].[H][H].C>[Pd].CO>[ClH:18].[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NC1CCNCC1
Reaction time: 1 h

Procedure:
10% w/w Palladium on charcoal (1.5 g) was added to a solution of the product from step (i) (10.0 g), 1 molar hydrochloric acid (21.5 ml) and methanol (150 ml) and the mixture hydrogenated at room temperature and pressure until the theoretical amount of hydrogen had been taken up. Charcoal was added, the mixture stirred for 1 hour then filtered through diatomaceous earth and the filtrate evaporated to dryness giving 4-acetylaminopiperidine hydrochloride, 8.64 g, as a sticky foam: NMR (CDCl3 +d6DMSO). δ 9,72(1H,b), 9.02(1H,b), 7.40(1H,bd), 3.87(1H,m), 3.30(2H,m), 2.81(2H,m), 1.86(4H,m), 1.80(3H,s); m/e 143 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][CH:12]([CH3:14])[CH3:13].[OH:15]O>C(O)(=O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15]
Reactant: OO
Reactant: Cc1cc(O)c(SCC(C)C)c(=O)o1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)c(S(=O)CC(C)C)c(=O)o1
Yield: 95 %

Procedure:
To a solution of 4-hydroxy-3-isobutylthio-6-methyl-2-pyrone (8.0 g., 0.0374 mole) in glacial acetic acid (50 ml.) was added 30% hydrogen peroxide (4.3 g., 0.0374 mole). The solution was allowed to stand for several days and then was diluted with water, filtered and the cake dried, yielding 8.2 g. (95 percent) of the desired product. Recrystallization from hexane gave the pure product as an off-white solid, m.p. 102°-103°C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])CC)C.[O:19]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[CH:38]([O:40]C(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>>[CH3:38][O:40][CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:33][CH2:32][CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:27][CH:28]=2)=[CH:11][C:10]=1[O:16][CH3:17])[C:4]([OH:3])=[O:18]
Reactant: OCCCOc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(O)cc1OC
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc(OCCCOc2ccc(Oc3ccccc3)cc2)ccc1CC(OC)C(=O)O

Procedure:
A mixture solution of 2-(4-Hydroxy-2-methoxy-benzyl)-butyric acid ethyl ester from Example 188, Step C and 3-(4-phenoxy-phenoxy)-propan-1-ol were allowed to react under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product which by the Standard hydrolysis procedure C (NaOH) yielded the title compound. MS (ES) for C26H28O7 [M+Na]+: 475.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([CH2:8][CH3:9])[C:5]([CH3:7])=[O:6].[CH2:11]([OH:14])[CH2:12]O.[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:10])[CH:4]([C:5]1([CH3:7])[O:14][CH2:11][CH2:12][O:6]1)[CH2:8][CH3:9])[CH3:15]
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(C(C)=O)C(=O)OC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC)C1(C)OCCO1
Temperature: 25 °C

Procedure:
Methyl-2-ethylacetoacetate (100 mL) was taken up in toluene (250 mL). Ethylene glycol (46.9 mL, 1.35 equiv.) and a catalytic amount of p-TsOH.H2O were added, and the mixture was refluxed overnight under Dean-Stark conditions. After cooling to ambient temperature, the mixture was washed with 5% aqueous NaHCO3 and saturated aqueous NaCl, the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by repeated vacuum distillation (118-128° C., 15 mbar), yielding 85.5 g of product. 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7 Hz, 3H), 1.28 (t, J=7 Hz, 3H), 1.40 (s, 3H), 1.59-1.83 (m, 2H), 2.56 (dd, J=11.5 and 4 Hz, 1H), 3.90-4.06 (m, 4H), 4.18 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=1[C:11]([OH:13])=O.C(N(CC)CC)C.Cl.[CH3:28][NH:29][O:30][CH3:31]>C(Cl)Cl.CN(C=O)C>[CH3:31][O:30][N:29]([CH3:28])[C:11](=[O:13])[C:10]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:9]=1[O:8][CH3:7]
Reactant: CNOC
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Oxalyl chloride (3.6 mL, 41.3 mmol) was added to a solution of 2,5-dimethoxybenzoic acid (6.00 g, 33.0 mmol) in DCM (100 mL). Then DMF (0.2 mL) was added to the mixture. The solution was stirred at room temperature for 2 h, and the solvent was removed under reduced pressure. The crude material was placed under vacuum for 30 min to remove the residual oxalyl chloride. Triethylamine (6.8 mL, 48.78 mmol) was added dropwise to the mixture of the residue and N,O-dimethylhydroxylamine hydrochloride (4.03 g, 41.32 mmol) in DCM (100 mL) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for additional 30 min. The reaction was diluted with DCM (50 mL), washed with H2O (2×100 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to yield N,2,5-trimethoxy-N-methylbenzamide (7.32 g, 99%) as clear oil which solidified over time. 1H NMR (CDCl3): δ 7.90 (m, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.58 (br s, 3H), 3.32 (br s, 3H).
Reaction SMILES: O[C@@H:2]([CH3:22])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2S,3S)-3-hydroxy-2-(5-phenylpentoxycarbonylamino)-butanoic acid (0.35 g, 1.13 mmol) in dry CH2Cl2 (35 mL), Et3N (0.47 mL, 3.39 mmol) and subsequently TBTU (0.43 g, 1.35 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.223 g, 76%), as white solid. MS (ESI) m/z: 292 [M−H]+; (ESI) m/z: 290 [M−H]−. 1H NMR (DMSO-d6): δ 1.28-1.39 (m, 2H), 1.48 (d, J=6.1 Hz, 3H), 1.54-1.65 (m, 4H), 2.57 (t, J=8.4, 16.2 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 4.64-4.80 (m, 2H), 7.14-7.23 (m, 3H), 7.23-7.33 (m, 2H), 8.05 (d, J=7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6].S(Cl)([Cl:33])=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:33])=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccc(CCCCCO)cc2)nc1)c1ccc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Nc1ccc(Oc2ccc(CCCCCCl)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 3,4-dichloro-N-{6-[4-(5-hydroxypentyl)-phenoxy]pyridin-3-yl}benzamide (6.83 g, 15.34 mmol) was added thionyl chloride (35 mL). The resulting solution was stirred for 20 minutes at room temperature, followed by stirring for 1 hour at 50° C. Excess thionyl chloride was evaporated, after which to the resulting residue was added ethyl acetate (100 mL). The obtained white powder was filtered, and washed with ethyl acetate, to thereby yield 6.98 g of the title compound.
Reaction SMILES: [C:1](N[C@H](C(O)=O)CCCC)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH2:17].O[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=N1.C(Cl)CCl>ClCCl>[C:1]([NH:19][C:23](=[O:17])[C@H:22]([CH2:27][CH2:26][CH2:25][CH3:24])[NH2:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCC[C@H](N)C(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine (Bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate and 50 mL of dichloromethane at 0° C. was added 3.45 g (1.2 mmol) of EDC. The resulting mixture was stirred at 0° C. for 1 hour and then ammonia gas was bubbled through the mixture for 10 min. The cooling bath was allowed to warm to room temperature and the mixture stirred for 18 hours. The mixture was evaporated at reduced pressure to dryness, triturated with 20% Na2CO3. The resulting solid was collected by filtration and washed with water to yield 2.69 g (11.7 mmol, 78%) of the title compound.