Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Li+].[OH-].N1C=CC=C(CC([N:21]2[CH2:28][S:27][CH2:26][C@@H:22]2[C:23]([OH:25])=[O:24])=O)C=1.[CH2:29]([O:36][C:37]1[CH:48]=[CH:47][C:40]([CH2:41][C@@H:42]([C:44]([OH:46])=[O:45])[NH2:43])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([N:21]2[CH2:28][S:27][CH2:26][C@@H:22]2[C:23]([OH:25])=[O:24])=[O:9])[CH:3]=1.[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][C@@H:42]([C:44]([OH:46])=[O:45])[NH2:43])=[CH:47][CH:48]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=C(O)[C@H]1CSCN1C(=O)Cc1cccnc1
Agent: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@H]1CSCN1C(=O)c1cccnc1

Procedure:
Intermediate 18 was coupled to nicotinic acid in a similar manner to that described for Intermediate 19, and subsequently hydrolysed with aqueous LiOH, as described for the compound of Example 7, to afford the title compound. δH (DMSO-d6) 8.78-8.55 (2 H, br m), 8.38 (1 H, br d J 7.8 Hz), 8.21-7.25 (7 H, m), 7.11 (2 H, d, J 8.5 Hz), 6.85 (2 H, br d, J 8.0 Hz), 5.02 (2H, s), 5.03-4.3 (4 H, m), 3.40-3.22 (1 H, br m), 3.03 (1 H, dd, J 13.8, 4.6 Hz) and 2.90-2.75 (2 H, m); m/z (ESI), 492 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([OH:35])([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-]>C1COCC1.CO.CN(C=O)C>[OH:35][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-Hydroxy-4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-1-yl)-acetic acid ethyl ester (137 mg, 0.27 mmol) was dissolved in THF/MeOH/DMF (3:1:1, 5 mL) and to the solution was added aqueous LiOH (4M, 1 mL). The mixture was stirred at room temperature for 18 hours, then the reaction mixture was filtered and purified by reverse-phase preparative HPLC to give the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (qd, J=12.38, 4.29 Hz, 1H) 1.42 (qd, J=12.51, 4.42 Hz, 1H) 1.77 (td, J=14.08, 1.14 Hz, 2H) 2.78 (m, 1H) 2.98 (td, J=12.63, 2.27 Hz, 1H) 3.29 (s, 2H) 3.87 (dd, J=11.37, 2.27 Hz, 1H) 4.39 (ddd, J=12.69, 1.83, 1.64 Hz, 1H) 7.04 (d, J=8.59 Hz, 1H) 7.32 (d, J=8.34 Hz, 2H) 7.61 (d, J=8.34 Hz, 2H) 7.80 (d, J=8.84 Hz, 1H) 7.99 (dd, J=8.72, 2.65 Hz, 1H) 8.55-8.62 (m, 1H) 8.57 (d, J=2.53 Hz, 1H) 8.92 (d, J=2.27 Hz, 1H) 9.93 (s, 1H); (M+H)+473.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCCc2ccccc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of 120 mg (0.74 mmol) of 1H-indole-7-carboxylic acid and 240 mg of TBTU (0.74 mmol) in 8 ml DMF, were added 0.64 ml (3.72 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 280 mg (0.74 mmol) of (4-tert-butyl-benzyl)-(3-phenyl-propyl)-amine were added. After stirring for 4 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 205 mg white solid (63%). MS (ISP) 425.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]4[C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(-c3ccccc3)n3c2c1OCC3c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (14 mg, 0.039 mmol), phenylboronic acid (5.6 mg, 0.046 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1:1) (2 mg, 0.002 mmol) and potassium carbonate (16 mg, 0.12 mmol) in 1,4-dioxane (0.2 mL), and water (0.1 mL). The resulting mixture was heated at 80° C. for 3 h. The reaction mixture was diluted with MeOH and purified on Preparative LCMS using pH 10 buffer to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:8]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:7]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])(O)[C:6]=2[CH:23]=1.[ClH:24]>C(O)C>[ClH:24].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:8]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]([CH:17]=[CH:18][CH2:19][N:20]([CH3:21])[CH3:22])[C:6]=2[CH:23]=1
Reactant: CN(C)CCCC1(O)c2cc(Br)ccc2OC12CCCCCC2
Agent: Cl
Solvent: CCO
Product: CN(C)CC=CC1c2cc(Br)ccc2OC12CCCCCC2

Procedure:
A solution of 2.58 g of 5-bromo-3-(3-dimethylaminopropyl)-3-hydroxy-spiro[benzofuran-2(3H),1'-cycloheptane] in 60 ml of absolute ethanol containing 5 ml of concentrated hydrochloric acid was refluxed under nitrogen for 1 hour, at which point TLC showed no starting material. The mixture was concentrated in vacuo to a solid. This material was triturated with ether, filtered and dried to afford 2.45 g of a solid, m.p. 207.5°-212° C. This material was combined with another batch of crude salt previously prepared in a similar manner. Recrystallization twice from absolute ethanol/ether afforded 1.38 g of a solid, m.p. 215°-217.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.C(Cl)[Cl:12].O>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(O)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Product: CC(Cl)c1ccc(Br)cc1

Procedure:
1-(4-Bromophenyl)ethanol (3.17 g, 15.8 mmol) was stirred in concentrated HCl (25 mL) and DCM (20 mL) at room temperature for 3 d. Water and DCM were added and the aqueous phase extracted with DCM. The combined organics were dried using a phase separator and concentrated in vacuo to give 1-Bromo-4-(1-chloroethyl)benzene (3.49 g) as a colourless oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([S:10][C:11]#[N:12])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.CN(C=O)C.C(N(CC)CC)C.[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])#[N:26]>C(O)(=O)C.O>[C:4]1([C:2]2[N:12]=[C:11]([CH:27]([C:25]#[N:26])[C:28]([O:30][CH3:31])=[O:29])[S:10][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC#N
Reactant: N#CSCC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C#N)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
90 parts of phenacyl thiocyanate are introduced into a mixture of 150 parts of DMF, 150 parts of triethylamine and 50 parts of methyl cyanoacetate. The mixture is then stirred for 4 hours at room temperature, after which it is introduced into water and the batch is acidified with acetic acid. The product which precipitates is filtered off and dried in an oven.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH2:22][CH2:23][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:31]([O:30][C:29]([NH:28][C@@H:24]([CH2:25][O:26][CH3:27])[CH2:23][NH:22][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(Nc2cccc(C)c2)n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a screw-top vial was added methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (0.28 g, 0.928 mmol), (R)-tert-Butyl 1-amino-3-methoxypropan-2-ylcarbamate (0.227 g, 1.114 mmol), and DIPEA (0.211 mL, 1.206 mmol) in DMF (3 mL). The resulting yellow solution was stirred at RT for 12 h, diluted with EtOAc (30 mL) and washed with water (2×20 mL) and brine (20 mL). The organic phase was dried with Na2SO4 and concentrated to give the title compound as thick yellow oil, which was used without further purification (470 mg). [M+H] calc'd for C24H31N5O5, 470. found, 470.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=2)[NH:26][CH:25]=1.O>CN(C)C=O>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:34])[CH:31]=2)[NH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
Polyphosphoric acid ethyl ester (40 ml) and 4-nitrophenol (6.3 g) were added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carboxylic acid (15 g) in dimethylformamide (70 ml) and the mixture was stirred at 80° C. for 24 hours. More polyphosphoric acid ethyl ester (20 ml) was added and the mixture stirred at 80° C. for 3 hours. The mixture was cooled, poured into ice and water (900 ml) and stirred for 1 hour with ice cooling. The resulting solid was filtered off and washed with boiling ethanol (1500 ml) and hot water (600 ml) to give the title compound (12.5 g) as pale yellow crystals m.p. 248°-251° C. T.L.C. Silica, ethyl acetate:2-propanol:water:ammonia (25:15:8:2) Rf 0.9.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[OH:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:14]
Reactant: COc1ccc2c(c1OC)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(c1O)CCC2=O
Temperature: 0 °C
Yield: 69.8 %

Procedure:
Under a nitrogen atmosphere 2,3-dihydro-4,5-dimethoxy-1H-inden-1-one (31.7 g) was dissolved in 600 ml of anhydrous 1,2-dichloroethane and cooled to 0° C. Aluminum chloride (44 g) was added in portions and the reaction mixture was heated to 60° C. for 17 hours, cooled to room temperature and poured into ice/water. After extraction with dichloromethane the organic layer was dried and evaporated. The residue was crystallized from ethyl acetate to give 20.5 g of 2,3-dihydro-4-hydroxy-5-methoxy-1H-inden-1-one, M.S. (C.I.) (M/Z): 179 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.CCOCC.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>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH2:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([C:35]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=5)[CH:26]=[CH:25][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CCCc1cnc(N2CCC(Cc3nc4ccc(Br)cc4o3)CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cnc(N2CCC(Cc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4o3)CC2)nc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
To a degassed solution of 6-bromo-2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]oxazole (0.15 g, 0.361 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.156 g, 0.506 mmol) and K2CO3 (0.125 g, 0.903 mmol) in dioxane (3.7 mL) and water (1.2 mL) was added Pd(Ph3P)4 (0.021 g, 0.018 mmol). The reaction mixture was stirred at 100° C. for 15 h. The reaction mixture was cooled to rt, and diluted with EtOAc/Ether (10 mL, 1:1 v/v). The organic layer was washed with NaHCO3 (aq, sat, 6 mL) and NaCl (saturated aqueous, 6 mL). It was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to afford desired product as a light yellow solid (180 mg, 96% yield). 1H NMR (400 MHz, chloroform-d) δ 8.14 (s, 2H), 7.61 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.3 Hz, 1H), 7.38-7.33 (m, 1H), 6.15-5.95 (m, 2H), 4.73 (d, J=13.4 Hz, 1H), 4.10 (s, 2H), 3.67 (t, J=5.6 Hz, 3H), 2.99-2.79 (m, 3H), 2.57 (s, 2H), 2.46-2.33 (m, 2H), 2.32-2.13 (m, 2H), 1.87 (d, J=11.2 Hz, 2H), 1.63-1.53 (m, 1H), 1.50 (s, 9H), 1.37 (dd, J=12.5, 4.0 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H). LCMS (m/z)=518 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reaction time: 8 h

Procedure:
3-Methyl-1,3-butanediol (1.5 mL, 14.06 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1.24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.06 mmol). The mixture is stirred overnight then washed with 1M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21

Procedure:
5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-1H-indole (D2) (600 mg), ethyl 3-bromopropanoate (374 μl), caesium carbonate (950 mg) and DMF were heated at 140° C. for 1 hour in a microwave reactor. A further 1 eq. of ethyl 3-bromopropanoate (187 μl) was added and the mixture heated for 30 minutes. The reaction mixture was then evaporated, dissolved in DCM and filtered to give the title compound (650 mg) as a brown solid. δH (CDCl3, 400 MHz): 1.21 (3H, t), 2.85 (2H, t), 4.13 (2H, q), 4.50 (2H, t), 6.61 (1H, d), 7.22 (1H, d), 7.44-7.52 (6H, m), 7.89-7.92 (1H, m), 7.98-8.02 (1H, m), 8.45-8.46 (1H, m). MS (ES): C26H20F3N3O3S requires 511; found 512 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[CH:61]=[C:60]([C:65]1[CH:66]=[C:67]([NH2:71])[CH:68]=[CH:69][CH:70]=1)[CH:59]=[CH:58]2>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:56]=[C:57]2[C:62](=[CH:63][CH:64]=1)[CH:61]=[C:60]([C:65]1[CH:66]=[C:67]([NH:71][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:68]=[CH:69][CH:70]=1)[CH:59]=[CH:58]2
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(OC(F)(F)F)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
DIEA (0.0115 mL, 0.067 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.06 mmol) and HATU (0.025 g, 0.067 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.015 g of product in 49% yield: LCMS (ESI) m/z 506 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:25])[C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH:5]=[O:6].[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:39](=[O:44])[CH2:40][O:41][CH2:42][CH3:43])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:39](=[O:44])[C@@H:40]([O:41][CH2:42][CH3:43])[C@@H:5]([C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[C:8]([CH3:25])[CH:7]=1)[OH:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 117) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-3-}3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 98.8%.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C(O)=O.[Cl-].[Li+].CO>[Pd].[C].[Pd].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 76.4 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (30 g, 0.11 mols), formic acid (9.7 g, 0.21 mols), lithium chloride (8.9 g, 0.21 mols) and methanol (180 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (6 g) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) (as metal palladium; 1 mass relative to 2,4-di-tert-butylphenyl methanesulfonate) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 9 hours. Water (10 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (30 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (16 g, yield 81% by mass). The result is shown in Table II-2.