Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: C#CCOc1ccccc1
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of CuI and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[N:11]([CH3:22])[C:10]=1[CH3:23])C1C=CC=CC=1.Cl>[Pd].CO>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])[N:11]([CH3:22])[C:10]=1[CH3:23]
Reactant: Cc1c(OCc2ccccc2)c(=O)cc(C(O)C(F)(F)F)n1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(O)c(=O)cc(C(O)C(F)(F)F)n1C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
A suspension of 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (190 mg, 0.58 mmol) and methanol (30 mL) was sonicated for a few min. The addition of a 6.00 N hydrochloric acid solution (50 μL, 0.30 mmol) gave a clear solution. To the solution was added Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 80 mg). The debenzylation reaction was conducted under a hydrogen pressure of 50 psi. The reaction was completed within 30 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The pH of the filtrate was adjusted to 6 by addition of a solution of 6.00 N sodium hydroxide (ca. 50 μL), and then concentrated in vacuo. The first crop of the solid was collected by suction filtration and washed with deionized water thoroughly to give 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (54 mg, 39% yield, HPLC Method 1 (Example 24), RT=9.4 min, HPLC purity (peak percent area): 95.8% at λ=280 nm). 1H NMR (CD3OD) δ ppm: 6.78 (s, 1H), 5.51 (q, J=6.5 Hz, 2H), 3.80 (s, 3H), 2.50 (s, 3H); MS-ESI (m/z) 238.2 [M+1]+, 169.2, 154.2 (100%), 140.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(CC2C=CC=CC=2)C=CC=CC=1>CO.Cl.CCOCC.[Pd]>[NH:16]1[CH2:17][CH:14]([CH:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:15]1
Reactant: COC(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cc(F)cc(F)c1
Agent: [Pd]
Agent: Cl
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reaction time: 18 h

Procedure:
A mixture of 0.406 g (1 mmol) of methyl (3,5-difluorophenyl)[1-(diphenylmethyl)azetidin-3-ylidene]acetate and 25 mg of 10% Pd/C in 10 mL of methanol and 1 mL of 1M HCl in ether was shaken under 40 psi H2 for 18 h. The mixture was filtered through CELITE and the solid residue was washed with 30 mL of methanol. The filtrate was concentrated to afford a mixture of the title compound and diphenylmethane, which was not separated but was used directly in the next step; Mass Spectrum: m/e=242 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([O-])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH2:4][O:3]1>C(OC(=O)C)(=O)C>[C:2]([O:7][CH2:18][C:12]1[C:11]([CH3:19])=[C:10]([O:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:20])([CH3:1])[O:3][CH2:4]2)[C:15]([CH3:16])=[CH:14][N:13]=1)(=[O:3])[CH3:1]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ncc(C)c(OCC2COC(C)(C)OC2)c1C
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 100.9 %

Procedure:
4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2,3,5-trimethylpyridine1-oxide (10.5 g, 37.4 mmol) was dissolved in acetic anhydride (100 mL) and the solution was stirred at 85° C. for 1.5 hours. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) and a desired fraction was concentrated to obtain the title compound (6.1 g, 50.4%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCC(=O)N1CCOCC1
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a mixture of 5-(N-t-butoxycarbonylamino)valeric acid (2.173 g) and morpholine (1.045 g) in anhydrous methylene chloride (22 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g) portionwise at 0°-5° C. After being stirred for 3 hours at the same temperature, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with 0.5N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 4-[5-(N-t-butoxycarbonylamino)valeryl]morpholine (1.668 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:15]([NH:14][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)=[O:16])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C=Nc1cccc2[nH]ccc12
Product: O=C(NCc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2[nH]ccc12

Procedure:
4-Chloro-3-(trifluoromethyl)benzylamine (0.27 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound. mp 197° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.42 (d, 2H), 6.52 (m, 1H), 6.96 (m, 3H), 7.25 (m, 1H), 7.56 (dd, 1H), 7.67 (dd, 1H), 7.70 (t, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 11.06 (s, 1H); MS (DCI+) m/z 368 (M+H). Anal. Calcd. for C17H13N3ClF3O: C, 55.52, H, 3.56; N, 11.43. Found C, 55.46; H, 3.65; N, 11.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])/[CH:5]=[N:6]/[S@@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH2:21]1COC[CH2:22]1.C([Mg]Br)C>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@@:7]([C:9]([CH3:10])([CH3:11])[CH3:12])=[O:8])[CH2:21][CH3:22])[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:18])[F:19]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CC[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 218 (3.8 g, 12 mmol) and THF (40 mL) cooled to −78° C. was added dropwise a solution of ethylmagnesium bromide (5.8 mL, 17 mmol) in ether and the solution was stirred for 1 h, quenched with water, and extracted with Et2O. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (35 to 40% EtOAc) to afford 3.5 g (84%) of (R)—N—((R)-1-(3-chloro-4-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide (220).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:29])[N:16](COC(=O)C(C)(C)C)[CH:17]=[N:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[CH2:4][CH2:3]1.N>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:29])[NH:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[CH2:4][CH2:3]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C)CC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCC1CCN(C)CC1
Yield: 101.3 %

Procedure:
A solution of 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (4.2 g, 9.7 mmol) in methanol saturated with ammonia (150 ml) was stirred overnight at ambient temperature. The volatiles were removed under vacuum and the residue was triturated with ether. The solid was filtered, washed with ether and dried under vacuum to give 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (3.12 g, 100%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[C:15](=[CH:18]OCC)[C:16]#[N:17])[CH3:12].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[NH2:17][C:16]1[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:22])=[CH:18][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[N:10]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)nc1N
Yield: 94.2 %

Procedure:
To a solution of 3-bromophenylhydrazine hydrochloride (2.25 g, 10.1 mmol) in acetic acid (15.1 mL) and water (5.04 mL) were added ethyl(ethoxymethylene)cyanoacetate (1.88 g, 11.1 mmol) and sodium acetate (3.02 g, 22.2 mmol), and the solution was refluxed for 16 hours. The reaction was cooled and quenched with ice-water. The precipitate formed was filtered, washed with water and dried under vacuum for 24 hours to give 2.95 g of the titled compound (93% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:11]([CH:13]([NH2:16])[CH2:14][CH3:15])[CH3:12].Cl>O>[CH2:11]([CH:13]([NH:16][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:14][CH3:15])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CCC(N)CC
Agent: Cl
Solvent: O
Product: CCC(CC)Nc1ccccc1[N+](=O)[O-]
Yield: 91 %

Procedure:
A solution of 158 grams of o-nitrochlorobenzene and 260 grams of 1-ethylpropylamine are refluxed together for 5 days. The solution is cooled and 500 ml. of water is added. Concentrated hydrochloric acid (10 milliliters) is added and the product separates out as an oil. The product is extracted with chloroform (2×200 milliliters), the extractions dried over MgSO4 and evaporated to yield 190 grams (91%) of product as an oil. The analytical sample is prepared by distillation of the crude oil, b.p. 1.8 mm Hg=148° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39]Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][CH2:39][C:38]1[C:37]([Cl:36])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:45])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
To a solution of 288 mg (0.74 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of dichloromethane, 0.21 ml (1.48 mmol) of triethylamine and 214 mg (0.89 mmol) of 2,6-dichlorobenzyl bromide were added, and the resulting mixture was stirred at room temperature for one day. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) to obtain 195 mg of 2-(2,6-dichlorobenzylamino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 48%).
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[O:15]=[C:16]1[C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:17]1>C1(C)C=CC=CC=1.C1COCC1>[C:11]([O:10][C:8]([CH:7]=[C:25]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:17][C:16]1=[O:15])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C1CCCCCCC(=O)C(=O)N1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCCCC(=CC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 0.42 h

Procedure:
Potassium hexamethyldisilylamide (40.5 mL of a 0.58M solution in toluene, 23.5 mmol) is added to THF (60 mL), and then cooled to 0° C. t-Butyl dimethylphosphonoacetate (4.6 mL, 23.5 mmol) is added dropwise, and the reaction is warned to room temperature and stirred for 25 minutes. Ethyl 2,3-di-oxo-1-azacyclodecane-10-carboxylate (2.83 g, 11.74 mmol) is added in THF (15 mL), and the reaction is stirred at room temperature for 2.5 hours. The reaction is quenched with saturated ammonium chloride, and then extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give ethyl 3-t-butoxycarbonylmethylidene-2-oxo-1-azacyclodecane-10-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: CC#CCOc1cc(Cl)ncn1
Solvent: CCO
Product: CC#CCOc1cc(Nc2ccccc2)ncn1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
In 1.1 ml of ethanol were dissolved 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.15 g of aniline, followed by heating under reflux for 7 hours. The reaction mxiture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.13 g of 4-anilino-6-(2-butynyloxy)pyrimidine (the present compound (53)), m.p.: 159.3° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[C:34]5[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:35]=5[N:36]=[CH:37][N:38]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)(C(C)(C)C)(C)C>C1COCC1.O.C(O)(=O)C.CCOC(C)=O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[C:34]5[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:35]=5[N:36]=[CH:37][N:38]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CO[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c3)c2)C1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CO)cc(C(F)(F)F)c3)c2)C1
Temperature: 32 °C

Procedure:
To a solution of tert-butyl 4-(1-(3-((tert-butyldimethylsilyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.252 g, 0.361 mmol) in 6 mL of THF and 14 mL of water, 26 mL of acetic acid is added. The mixture is heated to 32° C. for 5 h at which point the reaction is diluted with EtOAc, washed with water/pyridine, saturated sodium bicarbonate, brine and dried over sodium sulfate, concentrated to give the title compound. MS (ESI) m/z 584.2 (M+1).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].I[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.C(O)CO>[Cl-].[Na+].O.[Cu]I.C(Cl)Cl.C(O)(C)C>[N+:26]([C:22]1[CH:21]=[C:20]([NH:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])[CH:25]=[CH:24][CH:23]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: NCC(O)c1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(NCC(O)c2ccccc2)c1
Temperature: 75 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), K3PO4 (425 mg, 2.0 mmol), rac-2-amino-1-phenylethanol (140 mg, 1.02 mmol) and 1-iodo-3-nitrobenzene (302 mg, 1.25 mmol). Ethylene glycol (56 μL, 1.02 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 75° C. for 48 h. The reaction mixture was allowed to cool before dilution with 10 mL brine and extraction with methylene chloride (3×10 mL). The organic extracts were washed with 0.1 M NaOH (2×10 mL), washed with brine (1×15 mL), dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using methylene chloride/ethyl acetate (96:4). The product was obtained as an orange, viscous oil in 66% yield (172.8 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:40].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 79.7 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-(3-ethoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (165 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (261 mg, 79%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.17 (t, 3H), 1.96 (quintet, 2H), 2.39 (m, 4H), 2.46 (t, 2H), 3.60 (m, 6H), 3.93 (s, 3H), 4.19 (t, 2H), 4.40 (s, 2H), 6.17 (s, 2H), 7.17 (s, 1H), 7.20 (s, 1H), 7.82 (s, 1H), 8.33 (s, 1H), 9.54 (s, 1H); Mass Spectrum: M+H+ 555/557.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=NO)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].ClCC#N.CN(C)C=[O:25]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: ON=C(c1ccccc1)c1cnccn1
Agent: N#CCCl
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ccccc1)c1cnccn1
Reaction time: 1 h

Procedure:
Phenyl pyrazinyl ketone oxime (8.0 g) was stirred in 100 ml of dimethyl formamide containing 2.0 g of a 50% dispersion of sodium hydride in oil, for 0.5 hours at room temperature. Chloroacetonitrile (2.7 g) was added. The reaction mixture was stirred for 1 hour. The greater part of the dimethylformamide was evaporated under reduced pressure and the residue was treated with ether and water. The ether layer was separated and dried over magnesium sulphate. The product was recrystallized from a mixture of ether and petroleum ether (40°-60° C.), yielding pure phenyl pyrazinyl ketone, O-cyanomethyl oxime (5.6 g, m.p. 87°-89° C.).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35]([OH:37])=O>>[F:45][C:31]([F:30])([F:46])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:37]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-bis(trifluoromethyl)benzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-[3,5-bis(trifluoromethyl)benzoyl]-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 606 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:13]=1[O:14][CH:15]([CH3:18])[CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:13]=1[O:14][CH:15]([CH3:18])[CH:16]=[O:17]
Reactant: CC(CO)Oc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(C=O)Oc1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
4.68 g of DMSO were added under nitrogen to a stirred solution of 3.81 g of oxalyl chloride in 75 ml of methylene chloride at -60° C. to -50° C. After 2 minutes a solution of 6.4 g of 2-(2,4-dichlorophenoxy)propanol in 40 ml of methylene chloride was added. The mixture was stirred at -60° C. for a further 15 minutes and was then treated with 13.7 g of triethylamine After a further 5 minutes at -60° C. the mixture was allowed to warm to room temperature. 150 ml of water were added and the layers were separated. The aqueous layer was extracted with 150 ml of methylene chloride and the combined organic extracts were washed successively with sodium chloride solution, dilute hydrochloric acid, water, dilute sodium carbonate solution and water, dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica gel using ethyl acetate/n-hexane (1:4) for the elution. There were obtained 1.4 g of 2-(2,4-dichlorophenoxy)propionaldehyde, mp 87°-88° C.