Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10](N=C=NCCCN(C)C)[CH3:11].O>C(O)C.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(Br)s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
5-Bromothiophene-2-carboxylic acid (5.40 g) was dissolved in ethanol (50 ml), 4-dimethylaminopyridine (3.82 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.0 g) were successively added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water, 10% aqueous citric acid (twice), water, saturated aqueous sodium hydrogencarbonate and brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (5.99 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[CH3:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C=C2CCN(C(=O)Nc3cccnc3)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
To a solution of 2-(3-methyl-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (445 mg, 1.276 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (273 mg, 1.276 mmol) followed by triethylamine (0.53 mL, 3.83 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% acetone-70% hexane) to give the pure title compound (0.350 g, 58% yield). 1H NMR (500 MHz, CDCl3): δ 8.45 (m, 2H), 8.27 (s, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.02 (m, 1H), 6.92 (s, 1H), 6.84 (d, J=20 Hz, 2H), 6.47 (s, 1H), 6.38 (s, 1H), 3.16 (s, 2H), 3.52 (s, 2H), 2.61 (s, 2H), 2.47 (s, 2H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.87, 154.81, 153.01, 145.50, 143.77, 141.29, 139.84, 138.79, 137.99, 136.71, 127.58, 126.93, 124.77, 123.58, 122.62, 121.62, 120.13, 118.82, 111.38, 45.72, 44.70, 35.78, 29.20, 21.45; m/z (469.5, M+H+); HPLC: 98.5%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6](Br)[CH:7]([CH3:9])[CH3:8].C(#N)CCCCC#N.[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CBr
Reactant: CC(C)(C)N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: N#CCCCCC#N
Product: CC(C)CNC(C)(C)C
Reaction time: 12 h

Procedure:
A mixture of tert-butylamine (10.97 g, 0.15 mol), isobutyl bromide (13.70 g, 0.1 mol), adiponitrile (10.81 g, 0.1 mol) and tetrabutylammonium iodide (1.85 g, 5 mmol) was refluxed with stirring for 12 hours. Aqueous 5 M potassium hydroxide (30 ml, 0.15 mmol) was added and the mixture was extracted with n-pentane (2×50 ml). Three layers were formed. Adiponitrile (the middle layer) was recovered. The pentane solution was dried over anhydrous magnesium sulfate and the product was isolated by distillation to yield 9.5 g, (74%), bp 45-47° C./40 mm Hg; 1H NMR (CDCl3) δ0.91 (d, J=6.5 Hz, 6H, CH3), 1.08 (s, 9H, CH3), 1.64 (sep, J=6.5 Hz, 1H, CH), 2.34 (d, J=6.5 Hz, 2H, CH2).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]=2)=[O:20])[CH2:14][C:15](=O)[NH2:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:39])[C@@H:13]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]=2)=[O:20])[CH2:14][C:15]#[N:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(N)=O)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC#N)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{(S)-3-carbamoyl-2-[(6-cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester (67 mg) was dissolved in DCM (2 ml) under argon and Burgess reagent (103 mg) was added portionwise. After 1 h stirring at RT, the solvent was removed and the crude was purified by preparative TLC (EA/Hept 1/1) to offer 35 mg of the desired compound.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([NH2:32])=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2[O:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([NH:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1
Reactant: Brc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc4c(Nc5ccccc5)nn(C)c4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution/suspension of Pd2dba3 (9.30 mg, 0.01 mmol), 2-(dicyclohexylphosphino)-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (19.5 mg, 0.04 mmol), sodium tert-butoxide (46.0 mg, 0.48 mmol), 6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-methyl-1H-indazol-3-amine (Example 120, 119 mg, 0.34 mmol) and bromobenzene (53.4 mg, 0.34 mmol) in toluene (1 mL) was stirred at 100° C. for 16 h. After cooling to RT, the mixture was purified by silica gel chromatography (DCM/acetone: 100/0 to 70/30) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 427.3 (M+1). Mass Calc'd for C25H22N4O3: 426.47.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[N+:43]([O-])=O)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:39])([CH3:38])[O:11][Si:12]([CH3:37])([CH3:36])[O:13][Si:14]([CH3:35])([CH3:34])[O:15][Si:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([CH3:33])[CH:25]=1)([CH3:18])[CH3:17].[H][H]>>[NH2:43][C:42]1[CH:41]=[CH:40][C:4]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:39])([CH3:38])[O:11][Si:12]([CH3:36])([CH3:37])[O:13][Si:14]([CH3:35])([CH3:34])[O:15][Si:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([CH3:33])[CH:25]=2)([CH3:17])[CH3:18])=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc(OCCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc2ccc([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Product: Cc1cc(OCCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc2ccc(N)c(C)c2)ccc1N
Yield: 99.4 %

Procedure:
2.62 g of the above 2e (3.76 mmol) and 10 mL of a 10 wt % Pd/C ethyl acetate solution (0.0230 g) were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis[4-(4-amino-3-methylphenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3e) (2.38 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3e), and results are shown below.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](OCC)=[O:19])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[BH4-].[Li+].[Cl-].[NH4+].C(Cl)(Cl)Cl>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=2[C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2nc(NC(C)=O)sc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2ccc(CCCO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 6.5 h

Procedure:
To a suspension of ethyl(2E)-3-(4-{2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}phenyl)acrylate (306.5 mg) in tetrahydrofuran (3 ml) was added portionwise lithium borohydride (271 mg) at 0° C., and the mixture was stirred for 6.5 h at 20° C. The reaction mixture was poured into a mixture of saturated ammonium chloride aqueous solution (50 ml) and chloroform (50 ml) at 0° C. The organic layer was separeted, dried over maganesium sulfate and evaporarted to give a crude yellow solid (300 mg). The residue was purified by column chromatography over silica gel (80 ml) with hexane/ethyl acetate (1:2-1:5) as an eluent to give N-{4-[4-(3-hydroxypropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H-].[Na+].Br[CH2:16][C@@:17]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:19][CH:18]1[CH2:20]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:7]1([S:4]([C:3]2([S:2][CH3:1])[CH2:20][C@H:18]3[C@:17]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)([CH2:19]3)[CH2:16]2)(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccc([C@]2(CBr)CC2CBr)cc1Cl
Reactant: CSCS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 40 °C
Yield: 33.1 %

Procedure:
1-((Methylthio)methylsulfonyl)benzene (2.95 g, 14.6 mmole) was dissolved in dry dimethylforamide (DMF, 40 mL). Sodium hydride (1.75 g, 36.5 mmol) was added portion wise under nitrogen atmosphere at 0° C. The mass was gradually heated to 40° C. and maintained for 30 min at 40° C. A solution of (1S)-1,2-bis(bromomethyl)-1-(3,4-Dichlorophenyl)cyclopropane (5.65 g, 14.65 mmol) in DMF (10 mL) was added dropwise for 30 minutes at 0° C. The temperature of the reaction mass was brought to room temperature slowly and maintained for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (10:90)). The reaction mass was quenched with water. The aqueous layer was extracted with diethyl ether (2×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 8 g of crude oil that was purified by column chromatography (silica gel, ethyl acetate/hexane (4:96) to yield 2 g (33%) of product. 1H NMR δ(300 MHz,CDCl3): 1.73 (1H,m), 1.85 (2H,m), 2.04 (3H,s), 2.29 (2H,m), 2.54 (1H,m),2.88 (1H, dd, J=15 Hz), 7.12 (1H,d,J=3 Hz), 7.15 (1H,d,J=3 Hz), 7.25 (1H,m), 7.3 (1H,d,J=9 Hz), 7.55-7.57 (2H,m), 7.91 (2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[S:57]1[CH2:61][CH2:60][NH:59][CH2:58]1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:59]1[CH2:60][CH2:61][S:57][CH2:58]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CSCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(C(=O)N2CCSC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 67 %

Procedure:
Prepared analogously to Example 1g from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and thiazolidine in tetrahydrofuran. Yield: 67%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C20H18Cl2N4O2S (449.36); mass spectrum: (M+H)+=449/451/453 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][CH:10]([OH:12])[CH:11]=1)=[O:5])[CH3:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][CH:10]([O:12][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1=CC(O)CC1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC1=CC(OC2CCCCO2)CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
100 g of 2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-1-one was dissolved in 1000 ml dichloromethane, and added with 55 g of 3,4-dihydro-2H-pyran and 2 g of p-toluenesulfonic acid monohydrate, and then stirred at room temperature for about 3 hours. Upon completion of the reaction, the reaction mixture was washed with 400 ml of a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 2-ethoxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-1-one (138.5 g). 1H-NMR (CDCl3/TMS): δ 7.40-7.68 (m, 1H), 4.70˜5.02 (m, 2H), 4.15 (q, 2H), 3.88 (m, 1H), 3.54 (m,1H), 3.23 (q, 2H), 2.79 (m,1H), 2.37 (m, 1H), 1.77 (m, 2H), 1.55 (m, 4H), 1.25 (t, 3H).
Reaction SMILES: Cl.[SH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[Si](C)(C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24]>CC#N.CCOC(C)=O>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:23]([N:5]2[CH2:6][CH2:7][C@H:3]([SH:2])[CH2:4]2)=[O:24])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: S[C@H]1CCNC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](S)C1
Reaction time: 1 h
Yield: 72 %

Procedure:
A suspension of mercaptoamine hydrochloride 7 (589 mg, 4.22 mmol) in anhydrous MeCN (3.2 ml) was stirred under a N2 atmosphere with ice-bath cooling. The mixture was treated with N,N-diisopropylethylamine (1.69 ml, 9.71 mmol), stirred 5 min, and treated with chlorotrimethyl silane (0.70 ml, 5.52 mmol). After stirring 10 more minutes in the cold, the mixture was treated with a solution of p-nitrobenzyl chloroformate (910 mg, 4.22 mmol) in MeCN (1.0 ml) followed by more N,N-diisopropylethylamine (0.74 ml, 4.25 mmol). The resulting mixture was stirred in the cold for 15 minutes and at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with H2O, 1N HCl, 5% aqueous NaHCO3 and brine, dried with MgSO4, filtered, and evaporated (i.v.) to a yellow gum. The crude product was chromatographed on EM silica gel 60 (60 g) using 25:1 CH2Cl2 --EtOAc as eluting solvent to afford derivative 25 (858 mg, 72%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][C:44]2[O:45][C:41]3[C:40]([CH:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=3[N:43]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[C:27](=[O:43])[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1>CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:43])[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cc(I)c1=O
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)n1c(-c2cc([N+](=O)[O-])cn(COCC[Si](C)(C)C)c2=O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21

Procedure:
The title compound was prepared by the route outlined in Scheme 11 and using the experimental from Example 37, Step 3, with intermediate 5-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester (11a) (2.90 g, 8.3 mmol) and (6a), 3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one (3 g, 7.6 mmol). The resultant crude product was purified by flash chromatography on SiO2 with hexane—20% ethyl acetate/hexane (gradient) to afford after trituration using hexane, the title compound as a pale yellow solid, 3.67 g, 79%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].[OH-].[K+]>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: OCCC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Product: OCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 45 %

Procedure:
The process is performed as described in Example 2 (step 2.1). Starting with 25.6 g (113.90 mmol) of 1-bromo-3-(trifluoromethyl)benzene, 17.66 g (136.60 mmol) of 2-(4-piperidyl)ethanol, 26.24 g (273 mmol) of sodium tert-butoxide, 2.12 g (3.41 mmol) of BINAP and 1.04 g (1.14 mmol) of tris-(dibenzylideneacetone)dipalladium, and after chromatography on silica gel, eluting with a 25/75 mixture of ethyl acetate and cyclohexane, 17.90 g of an orange-coloured oily residue are obtained. This residue is then taken up in 100 ml of methanol, a solution of 4.24 g of potassium hydroxide in 15 ml of methanol is then added and stirring is continued at room temperature for 1 hour. The mixture is concentrated under reduced pressure and the residue is then taken up in chloroform and aqueous hydrochloric acid solution (1N). The organic phase is separated out and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. 14 g of product are obtained in the form of a dark yellow oil, which is used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:16](=[O:23])[O:17]CC(Cl)(Cl)Cl)[CH2:9][C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:6])[CH:2]=[CH2:3]>C(O)(=O)C.[Zn]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:16]([OH:23])=[O:17])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)C[C@H](NC(=O)OCC=C)C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCOC(=O)C[C@H](NC(=O)OCC=C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Allyl(S)-3-(allyloxycarbonylamino)-4-oxo-4-(2,2,2-trichloroethoxy)butyrate (350 mg, 9.02×10−4 mol) obtained from Example 20-(2) was dissolved in acetic acid (1.8 ml), then zinc powder (350 mg) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. The insoluble material was filtered off and washed with ethyl acetate. The filtrates were combined, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with a 0.2N aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford the crude title compound (180 mg, 78% yield) as a pale yellow oil.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:18][NH:19][C:20]([NH2:22])=[S:21]>O1CCCC1>[CH3:18][NH:19][C:20]1[S:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:22]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: CNC(N)=S
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NC)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (0.65 g, 2.2 mmol) in 20 mL of tetrahydrofuran was added N-methylthiourea (0.20 g, 2.2 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (0.46 g, 73%). MS (ESI) 288.3 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCCN
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: Cl
Product: CCOC(=O)CCCNC(=O)c1ccc(CCl)cc1

Procedure:
Ethyl 4-(4-(chloromethyl)benzamido)butanoate 13g was prepared by coupling 4-(chloromethyl)benzoic acid 24 with ethyl 4-aminobutyrate 26 according to the procedure described for the compound 13e in Example 21 (Scheme 8). The compound 13g was isolated as colorless oil in 89% yield (2.52 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=6.8 Hz); 1.96 (2H, quint, J=7.2 Hz); 2.44 (2H, t, J=7.2 Hz); 3.52 (2H, t, J=7.2 Hz); 4.10 (2H, q, J=6.8 Hz); 4.60 (2H, s); 6.62 (1H, broad s); 7.44 (1H, s); 7.46 (1H, s); 7.76 (1H, s); 7.78 (1H, s). MS (ESI): m/z=284.00 (M+H+).