Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([CH:10]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C(CCc1ccccc1)c1ccc(-c2ccccc2)c(F)c1

Procedure:
1.93 g of 60% oily sodium hydride was suspended in 70 ml of dimethylformamide, and a solution of 10.0 g of 2-fluoro-4-biphenylyl acetone in 30 ml of dimethylformamide, was added under cooling with ice with stirring, followed by stirring at room temperature for 50 minutes. Then, 7.20 ml of phenethyl bromide was added, followed by stirring at room temperature for 18 hours. The reaction solution was extracted by an addition of water and ethyl ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 10.9 g of the above identified compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[NH:9]2)=[CH:5][C:4]=1[C:25]([NH2:27])=[O:26].[H-].[Na+].Cl.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35]Cl)[CH3:32].O>CN(C=O)C>[CH2:31]([N:33]([CH2:37][CH2:38][N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:25]([NH2:27])=[O:26])=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[C:8]1[N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH2:34][CH3:35])[CH3:32]
Reactant: COc1cc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2cc1C(N)=O
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCn1c(N2CCC(Cc3ccccc3)CC2)cc2cc(C(N)=O)c(OC)cc21
Reaction time: 18 h
Yield: 55.2 %

Procedure:
0.3 g (0.862 mmol) of 6-methoxy-(4-benzylpiperidinyl)-indole-5-carboxamide was dissolved in 20 mL dry DMF. It was cooled in an ice-bath and reacted with 0.12 g NaH (3 mmol, 60% suspension). 0.172 mg (1 mmol) of 2-(diethylamino)-ethylchloride hydrochloride was added and the mixture was stirred for 18 h. The reaction mixture was poured in to water and extracted with dichloromethane (3×75 mL). The combined extract was washed again with water, dried over anhydrous MgSO4, evaporated and purified by silica gel chromatography on a chromatotron using CH2Cl2-Methanol (95:5) to yield 0.22 g of the desired product. It was converted to the HCl salt and lyophilized, M+ 448.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22]([C:38]([CH3:40])=[CH2:39])[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>CCO.[Pd]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22]([CH:38]([CH3:40])[CH3:39])[N:21]=3)[C@H:14]2[CH3:41])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(C)C)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (20 mg, 0.033 mmol) in anhydrous EtOH (3 mL), was added a catalytic amount of 10% of palladium on carbon. The mixture was stirred under 1 atm of hydrogen for 2 h. The reaction mixture was filtered through Celite. The solvent was concentrated in vacuo. Flash chromatography of the residue (Si, hexanes/EtOAc) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropylpyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=613.2; found=613.3 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 7.88 (s, 1H); 7.75 (s, 2H); 7.45 (d, J=7.8 Hz, 1H); 7.17 (d, J=7.8 Hz, 1H); 7.04 (br, s, 0.5H); 6.98 (br, s, 0.5H); 6.70 (s, 0.5H); 6.68 (s, 0.5H); 5.72-5.56 (br, m, 1H); 4.95-4.76 (br, m, 1H); 4.41 (br, m, 0.5H); 4.23 (br, m, 0.5H); 4.18-3.89 (br, m, 1H); 3.77 (s, 3H); 3.25-3.19 (m, 1H); 3.16-3.08 (m, 1H); 1.37 (m, 6H); 1.28 (d, J=6.9 Hz, 6H); 0.73 (br, s, 1.5H); 0.62 (br, s, 1.5H).
Reaction SMILES: [CH2:1]([N:5]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:11]=1[O:19][CH3:20])[C:6]([CH2:8][NH2:9])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:21][O:22][C:23]([CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36])=[O:24]>>[CH2:1]([N:5]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:11]=1[O:19][CH3:20])[C:6]([CH2:8][NH:9][C:35]([C:27]1[N:26]([CH2:25][C:23]([O:22][CH3:21])=[O:24])[C:34]2[C:29]([CH:28]=1)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:36])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)CN)c1c(OC)cc(C)cc1OC
Reactant: COC(=O)Cn1c(C(=O)O)cc2ccccc21
Product: CCCCN(C(=O)CNC(=O)c1cc2ccccc2n1CC(=O)OC)c1c(OC)cc(C)cc1OC
Yield: 90 %

Procedure:
This product is prepared according to the process described in EXAMPLE 1 from [butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl]methylamine and 1-(methoxycarbonylmethyl)-2-indolecarboxylic acid; M.p.=139° C.; Yield: 90%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH2:5][OH:6].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br>CN(C)C=O>[CH3:3][C:4]([CH3:16])([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH3:15])=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([F:26])=[C:18]([Br:17])[CH:19]=1
Reactant: Fc1ccc(CBr)cc1Br
Reactant: CCOc1ccc(C(C)(C)CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Br)c2)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
657 Milligrams of sodium hydride (as 60% oil suspension) was added to 10 ml of dimethylformamide, and 3.19 g of 2,2-dimethyl-2-(4-ethoxyphenyl)ethanol was added dropwise. Thereafter, the reaction solution was warmed to 50° C. and stirred for 10 minutes, and 4.0 g of 3-bromo-4-fluorobenzyl bromide was added dropwise thereto at 20° C. After completion of the dropwise addition, stirring was continued at 50° C. for further 5 hours, and the reaction solution was then poured into a 5% hydrochloric acid/ice water mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride liquor and dried over anhydrous magnesium sulfate. After removing the solvent by evaporation, the residual oil was purified by column chromatography on a column packed with 60 g of silica gel to obtain 2.37 g of 3-bromo-4-fluorobenzyl 2,2-dimethyl-2-(4-ethoxyphenyl)ethyl ether. 1H-NMR spectrum (CDCl3, TMS). δ 7.4-6.5 (7H, m), δ 4.30 (2H, s), δ 3.99 (2H, q), δ 3.34 (2H, s), δ 1.36 (3H, t), δ 1.30 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.Cl[C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][C:33]=2[C:34]#[N:35])=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyl alcohol (4.00 g), 2-chloro-3-cyanopyridine (2.41 g) and N,N-dimethylformamide (80 mL) was gradually added sodium hydride (60%, oil, 700 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 2 hrs, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. Recrystallization from ethyl acetate-isopropyl ether gave colorless prism crystals (4.02 g, 78%) of 2-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyloxy]nicotinonitrile. melting point: 145-146° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:9]([S:12][CH2:13][C:14]([OH:16])=[O:15])=[N:10][N:11]=1.[C:30]([O:49][CH2:50][CH:51]([CH2:53]O)[OH:52])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>N1C=CC=CC=1>[C:30]([O:49][CH2:50][CH:51]([OH:52])[CH2:53][O:15][C:14](=[O:16])[CH2:13][S:12][C:9]1[N:8]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:7]([Br:6])=[N:11][N:10]=1)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (2.4 mmol) is added dropwise over 5 mins to a solution of 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in pyridine (20 mL) at 0° C. The mixture is stirred at 0° C. for a further 1 hour and then glyceryl monooleate (715 mg, 2.0 mmol) dissolved in pyridine (5 mL) is added dropwise over 5 mins. The mixture is stirred at 0° C. for a further 3 hours and 1 hour at 20° C. and then quenched by addition of water (1 mL). Volatile solvents are removed in vacuo and DCM (200 mL) added. The organic phase is washed with water (1×50 mL), saturated sodium carbonate solution (1×50 mL) and brine (1×50 mL), dried over Na2SO4, concentrated to dryness and purified by column chromatography (acetone/DCM eluent) to provide 3-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetoxy)-2-hydroxypropyl oleate.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.OC(C(F)(F)F)=O.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:46][CH:45]=1)([O:42][CH3:43])=[O:41]>>[C:40]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH:53]2[CH2:54][CH2:55][N:56]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:57][CH2:58]2)=[CH:46][CH:45]=1)([O:42][CH3:43])=[O:41]
Reactant: COC(=O)c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCCC2CCN(C[C@H]3CN([C@@H](C(=O)OCc4ccc(OC)cc4)C4CCCCC4)C[C@@H]3c3ccccc3)CC2)cc1
Yield: 44.1 %

Procedure:
The title compound was prepared from 50 mg (0.11 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 0.1 mol of 4-(3-((4-carbomethoxy)phenyl) propyl)piperidine TFA (from EXAMPLE 29, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to afford 33 mg (48%) of the title compound: 1H NMR (500 MHz), 0.60-1.28 (9H), 1.46-1.80 (11H), 1.95 (app d, J=13.0, 1H),2.18-2.36 (3H), 2.54 (dd, J=6.5,9.0, 1H), 2.60-2.64 (m, 2H), 2.66 (t, J=8.5, 2H), 2.77-2.82 (m, 2H), 3.13-3.21 (3H), 3.80 (s, 3H), 3.90 (s, 3H), 5.09 (ABq, J=12.0, 2H), 6.87 (d, J=9.0, 2H), 7.15-7.23 (5H), 7.25 (d, J=7.0, 2H), 7.32 (d, J=9.0,21), 7.93 (d, J=7.0, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1
Reactant: OCCON=Cc1ccc2ccccc2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 478 mg of 2-(2-quinolylmethyleneaminooxy)ethanol (prepared as described in Preparation 2), 1.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 638 mg of triphenylphosphine and 423 mg of diethyl azodicarboxylate, 1.12 g of the title compound were obtained as a crystalline powder, melting at 127°-130° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].[OH-].[K+]>C(O)C.O>[CH2:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCCCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCCCCCCCOc1ccc(O)cc1
Yield: 36.4 %

Procedure:
Hydroquinone (37.65 g, 342 mmol) and dec-9-enyl bromide (25 g, 114 mmol) were dissolved in ethanol (150 ml) with warming under a nitrogen atmosphere. The solution was heated under reflux and a solution of potassium hydroxide (6.83 g, 121 mmol) in water (20 ml) was added dropwise over 1 h. The resulting suspension was heated under reflux (3 H) then poured on to water (500 ml) and extracted with ether (3×100 ml). The combined extracts were dried (MgSO4), evaporated in vacuo and the residue extracted with heptane (300 ml). On cooling, it afforded a first crop of the phenol (10.31 g). The remaining material was chromatographed (flash grade silica gel, petroleum ether 40-60° C./diethyl ether 3/2). 2 was isolated as white plates (Rf=0.57). Combined yield=15.61 g (55%). Mp=54° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:30])([CH3:29])[C@@H:11]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:30])([CH3:29])[C@@H:11]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(2-methylpropanoyloxy)butanoate (36c) (0.23 g, 0.49 mmol) dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 64 mg (0.98 mmol) of sodium azide (NaN3). After work-up, the crude material (36d) was obtained and used in the next step without further purification. MS (ESI) m/z 504.01 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH2:37]([NH2:40])[CH2:38][NH2:39].C(P(=O)(OCC)OCC)#N>>[NH2:39][CH2:38][CH2:37][NH:40][C:27]([C:23]1[CH:22]=[C:21]([C:20]2[N:12]([CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[N:13]=[C:14]3[C:19]=2[C:18](=[O:30])[N:17]([CH3:31])[C:16](=[O:32])[N:15]3[CH2:33][CH:34]([CH3:35])[CH3:36])[N:25]([CH3:26])[CH:24]=1)=[O:29]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: NCCN
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and ethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 551.15 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[O:28][C:24]=2[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[O:28][C:24]=2[CH:23]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2cc3ccc(F)cc3o2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in dioxane (2 mL) was added 2-(6-fluoro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, crude), Pd(PPh3)4 (20 mg, 0.02 mmol), K3PO4 (140 mg, 0.66 mmol) under nitrogen atmosphere. After stirring 40 min at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (55 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2].[C:26]1([CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>ClCCl>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:20]1[CH2:21][CH2:22][N:23]([C:33](=[O:34])[CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][CH3:37])[CH2:24][CH2:25]1)[O:9][C@H:10]2[CH2:16][NH:17][CH:18]=[O:19])([CH3:3])[CH3:2]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc2c(c1OC(C)C)C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C(=O)N1CCC([C@@H]2Cc3c(ccc(C)c3OC(C)C)[C@H](CNC=O)O2)CC1)c1ccccc1
Temperature: 10 °C

Procedure:
Stir a solution of N-((1R,3S)-5-isopropoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (200 mg, 0.58 mmole) in dichloromethane (3 mL), cool to 10° C. and add 2-phenylbutyryl chloride (115 mg, 0.64 mmole) and triethylamine (88 mg, 0.87 mmole). Allow to warm to room temperature and pour into dilute HCl. Separate the layers an extract the aqueous layer two times with 4 mL of dichloromethane. Wash the combined organic extracts with water and dry over Na2SO4. Purify the crude product on a 10 g silica gel column (eluting with ethyl acetate:heptane 3:1). Collect the appropriate fractions and concentrate to obtain the title compound. It was used without further purification in the next step.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>>[OH:13][C@H:3]([CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH2:2][NH:1][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: Cc1ccc(OC[C@@H](O)CN)cn1
Product: Cc1ccc(OC[C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)cn1

Procedure:
The title compound was prepared from (2S)-1-amino-3-[(6-methyl-3-pyridinyl)oxy]-2-propanol (which was obtained in Example 127) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp 87° C. (decomposed); 1H NMR (400 MHz, DMSO-d6) δ 1.44–1.49 (m, 2 H), 1.93–1.97 (m, 2 H), 2.38 (s, 3 H), 2.64–2.70 (m, 2 H), 2.77–2.95 (m, 4 H), 3.23–3.27 (m, 1H), 3.35 (brs, 2 H), 3.64–3.67 (m, 2H), 3.93–4.02 (m, 3 H), 4.58–4.62 (m, 1 H), 6.84–6.86 (m, 2 H), 7.03–7.05 (m, 2 H), 7.15–7.17 (m, 1 H), 7.27–7.30 (m, 1 H), 8.14–8.15 (m, 1 H); MS (ES) m/z: 469 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Bromoanisole (9.35 g, 50.0 mmol, 1.0 eq) was dissolved in anhydrous THF (200 mL). Me3SiCl (12.7 mL, 100.0 mmol, 2.0 eq) was added at 0° C. followed by n-BuLi (2.5 M in hexanes, 40 mL, 100.0 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water (150 mL) was then added, the organic layer was separated and the aqueous layer was extracted with Et2O (150 mL×2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-methoxyphenyl)trimethylsilane as a light yellow oil (8.1 g, 90% yield). 1H NMR (300 MHz, CDCl3) δ: 7.48 (d, J=11.2 Hz, 2H), 6.95 (d, J=11.2 Hz, 2H), 3.84 (s, 3H), 0.27 (s, 9H).