Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@@H:14]2[CH:18]=[C:17]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH2:16][N:15]2[C:27]([O:29]CC2C=CC=CC=2)=[O:28])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=C1CN(C(O[C:46]([CH3:49])([CH3:48])[CH3:47])=O)[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)C1>>[C@H:1]1([NH:11][C:12]([C@@H:14]2[CH:18]=[C:17]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH2:16][N:15]2[C:27]([O:29][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:28])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 61 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound B of Example 22, (S)-tert-butyl 4-oxo-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (3.38 g, 9.43 mmol) was converted to the title compound (2.82 g, 61%). MS (ESI+) m/z 491.2 (M+H)+.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:15])[CH:7]=1>O1CCCC1>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
Borane-dimethyl sulfide complex (2M in THF; 116 mL, 0.232 mol) is added slowly to a solution of 4-bromo-2-methylbenzoic acid (24.3 g, 0.113 mol) in anhydrous tetrahydrofuran (THF, 146 mL) at 3° C. After stirring cold for 10 min the cooling bath is removed and the reaction is allowed to warm slowly to ambient temperature. After 1 hour, the solution is cooled to 5° C., and water (100 mL) is added slowly. Ethyl acetate (100 mL) is added and the phases are separated. The organic layer is washed with saturated aqueous NaHCO3 solution (200 mL) and dried over Na2SO4. Filtration and concentration under reduced pressure gives a residue which is purified by filtration through a short pad of silica eluting with 15% ethyl acetate/iso-hexane to give the title compound (20.7 g, 91.2% yield). MS (m/z): 183/185 (M+1-18).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([C:14]([OH:16])=[O:15])[CH2:10]2)=[O:5])[CH3:2].[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH:7]12[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]([C:14]([O:16][CH:22]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)=[O:15])[CH2:8]2
Reactant: OC1C=CCCC1
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CC(C(=O)OC1C=CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-4) (1.88 g, 8.27 mmol) in dichloromethane (30.0 mL) was added 2-cyclohexen-1-ol (0.812 g, 8.27 mmol, Aldrich), EDC (2.38 g, 12.4 mmol), and DMAP (0.100 g). The mixture was stirred at room temperature overnight and quenched with EtOAc (200 mL). The organic solution was washed with a 5% aqueous HCl solution (100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL), and dried over anhydrous MgSO4, and concentrated. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-5) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[N:9]2[CH:12]([CH3:17])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:4][CH:3]=1.O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:17][CH:12]1[N:9]2[C:10]3[C:5]([CH2:6][CH2:7][C:8]2=[N:15][NH:14][C:13]1=[O:16])=[CH:4][CH:3]=[C:2]([NH:1][CH:19]1[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22]1)[CH:11]=3
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2CCc3ccc(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2CCc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A solution of 9-amino-1-methyl-5,6-dihydro-1H-[1,2,4]triazino[4,3-a]quinolin-2(3H)-one (0.035 g, 0.152 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.078 g, 0.45 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was stirred for 1 h at rt. Sodium cyanoborohydride (0.028 g, 0.456 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The solution was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 3-(1-methyl-2-oxo-2,3,5,6-tetrahydro-1H-[1,2,4]triazino[4,3-a]quinolin-9-ylamino)azetidine-1-carboxylate (0.020 g, 34%). LC/MS (Table 1, Method 2) Rt=1.104 min; MS m/z: 386 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:34]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])=[CH:4][N:3]=1.[CH3:36][O-:37].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:37][CH3:36])=[C:14]([CH:34]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])=[CH:4][N:3]=1
Reactant: Nc1ncc(C#Cc2ccc(F)c(C(=O)Nc3cc(C(F)(F)F)ccc3N3CCCCC3)c2)cn1
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc(C#Cc2cnc(N)nc2)cc1C(=O)Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 16 h

Procedure:
A mixture of 5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.14 g, 0.29 mmol) and NaOMe (0.5 M solution in methanol, 2.0 mL, 1.0 mmol) in a sealed tube was heated to reflux. After 16 h, the reaction was cooled and partitioned between EtOAc and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The material was purified by preparative TLC, eluting with 30% acetone/dichloromethane to give 5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide as a white solid. MS m/z=496 [M+H]+. Calc'd for C26H24F3N5O2: 495.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N+:15]([O-:27])=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3ccncc3c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2ccc(OCc3ccccc3)cc2c1
Yield: 98.1 %

Procedure:
A solution of 7-benzyloxyisoquinoline (International Patent Application publication no. WO 94/20459) (0.50 g, 2.13 mmol) in CH2Cl2 (20 mL) was stirred with 3-chloroperbenzoic acid (mCPBA) (1.1 g, 3.19 mmol) at room temperature for 2.5 h. The mixture was diluted with CH2Cl2, and then washed with sodium dithionite (1 M), potassium carbonate (1 M) and brine. The organic layer was dried over MgSO4 and evaporated in vacuo to leave 7-benzyloxyisoquinoline N-oxide (0.521 g, 2.09 mmol) as a cream-coloured powder.
Reaction SMILES: [OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[Br-].[Cl:27]C1C=C(C=CC=1Cl)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[OH:1][C:2]1[CH2:6][O:5][C:4](=[O:7])[C:3]=1[C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[C:22]([Cl:27])[CH:23]=1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl
Reactant: O=C(CCCCCCCCCc1ccc(Cl)cc1)C1=C(O)COC1=O
Agent: [Br-]
Product: O=C(CCCCCCCCCc1ccc(Cl)c(Cl)c1)C1=C(O)COC1=O

Procedure:
Using the procedure of Example 41 for the synthesis of 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodecyl]-2(5H)-furanone above, but using 3,4-dichlorobenzyltriphenylphosphonium bromide in place of 4-chlorobenzyltriphenylphosphonium chloride, there is obtained the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][CH2:16][C@H:17]([OH:49])[C@H:18]([C@H:20]1[O:22][C@@H:21]1[CH2:23][C@@H:24](/[CH:26]=[CH:27]/[CH:28]=[C:29](/[C@H:31]1[O:43][C:41](=[O:42])[CH2:40][C@H:39]([OH:44])[CH2:38][CH2:37][C@:36]([OH:46])([CH3:45])[C@@H:35]([OH:47])[CH2:34][CH2:33][C@@H:32]1[CH3:48])\[CH3:30])[CH3:25])[CH3:19].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][CH2:16][C@H:17]([OH:49])[C@H:18]([C@H:20]1[O:22][C@@H:21]1[CH2:23][C@@H:24](/[CH:26]=[CH:27]/[CH:28]=[C:29](/[C@H:31]1[O:43][C:41](=[O:42])[CH2:40][C@H:39]([OH:44])[CH2:38][CH2:37][C@:36]([OH:46])([CH3:45])[C@@H:35]([O:47][C:8]([CH3:9])=[O:10])[CH2:34][CH2:33][C@@H:32]1[CH3:48])\[CH3:30])[CH3:25])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](O)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)/C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)CC[C@@H]1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](O)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)/C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)CC[C@@H]1C
Temperature: 0 °C
Yield: 82 %

Procedure:
Triethylamine (17.2 μl, 123 μmol), acetic anhydride (5.83 μl, 616 μmol) and 4-dimethylaminopyridine (1.50 mg, 12.3 μmol) were added to anhydrous dichloromethane (2.00 ml) solution of pladienolide A (30.5 mg, 61.6 μmol) under stirring at 0° C. After the reaction solution was stirred at 0° C. for one hour, it was poured into a saturated sodium hydrogen carbonate aqueous solution, which was then extracted with ethyl acetate. After the organic layer was washed with brine, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:acetone=3:1→2:1) to obtain the title compound (27.2 mg) as a colorless oil. This was obtained as a white amorphous by purifying by HPLC (Shiseido, commercial name CAPCELL PAK C18SG120; acetonitrile:water=45:55) followed by performing lyophilization.
Reaction SMILES: [NH:1]1[CH2:85][CH2:84][CH2:83][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:82][CH2:81][CH2:80][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:76]([O:78]C)=[O:77])[CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O.N>O>[NH:1]1[CH2:85][CH2:84][CH2:83][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:82][CH2:81][CH2:80][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:76]([OH:78])=[O:77])[CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 0.67 h

Procedure:
370 mg of H-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys-OMe×5 TFA are dissolved in 8 ml of H2O. The pH value is increased to 5.0 with 0.3N NH3, whereupon 40 μl of a 1% aqueous solution of trypsin are added and the pH value is maintained constant by means of a pH stat with the addition of 0.3N NH3. The absorption of base is complete after approximately 40 minutes. 1 ml of glacial acetic acid is added, the whole is heated for 2 minutes in a boiling water bath, concentrated to approximately 3 ml and lyophilised. The residue is dissolved in 3 ml of 0.05N AcOH, converted into the acetate by slowly being filtered through a column (φ=1 cm, length=10 cm) of weakly basic ion exchanger (Merck No. II) in acetate form, and the eluate is again lyophilised, yielding H-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys-OH×AcOH in the form of amorphous white powder; Rf (D)=0.12; Rf (K)=0.14.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31]>>[NH2:28][CH2:29][C@@H:30]([CH3:31])[O:32][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([CH3:27])[CH:14]=1)=[N:5][CH:6]=[N:7]2
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: C[C@@H](O)CN
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN)c34)cc2C)cn1
Yield: 77 %

Procedure:
The procedure described in Example 103 (preparation of starting materials) was repeated using 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials) and (2R)-1-aminopropan-2-ol to give 5-[(1R)-2-amino-1-methylethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine in 77% yield; Mass spectrum: MH+ 416
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=O)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([CH2:27][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOCc1cccc(Cn2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccn1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccccn4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and pyridine-2-carbaldehyde. MS (ESI) m/z 470.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)=[CH:26]1>ClCCl>[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([N:9]3[CH2:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[NH:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=4)=[O:35])=[CH:32][CH:31]=2)=[CH:26]1
Reactant: O=C(Cl)c1ccc(-c2ccsc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccsc2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(3-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred 16 hours at room temperature and diluted with dichloromethane (50 ml). The solution is washed with 30 ml each of H2O, 2N HCl, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue purified by chromatography on silica gel with hexane-ethyl acetate as eluent to give a solid.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([C:25]([F:28])([F:27])[F:26])[CH:10]=3)=[N:5][N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:3]1=[O:37].CC(O)=[O:40].OO>O1CCOCC1>[OH:40][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[C:25]([F:28])([F:26])[F:27])[O:8][CH2:7][C:6]1[N:15]2[CH:2]([CH3:1])[C:3](=[O:37])[N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:5]=1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: CC(=O)O
Agent: OO
Solvent: C1COCCO1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(O)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.500 g, 0.923 mmol) in dioxane (25 mL) was added AcOH (2.5 mL) and hydrogen peroxide (30%, 5 mL) and the reaction mixture was stirred at ambient temperature overnight. The solution was quenched by the addition of saturated Na2SO3 solution and the volatiles were evaporated in vacuo. The aqueous residue was extracted with EtOAc (3×20 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-20% EtOAc in petroleum ether) to give 6-hydroxy-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.200 g, 50%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.15 (s, 1H), 6.59 (s, 1H), 6.00 (s, 1H), 5.14 (m, 2H), 4.69 (m, 2H), 4.56 (m, 1H), 3.69 (t, J=8.4 Hz, 2H), 1.53 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.04 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.O[CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.C([SiH](CC)CC)C.N>>[C:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([N:17]2[CH2:16][CH2:15][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=3)[CH2:9]2)[CH3:32])=[CH:21][CH:22]=1)([O:30][CH3:31])=[O:29]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: CC[SiH](CC)CC
Agent: N
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reaction time: 6 h

Procedure:
Prepared analogously to Example 3 by reaction of 11.6 g (0.043 mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole with 23 g (0.086 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine. To complete the reaction the mixture is heated to boiling for 6 hours. It is then concentrated in vacuo, and the resulting residue is dissolved in 85 ml of trifluoroacetic acid and, at room temperature, 7 g (0.06 mol) of triethylsilane are added. After 90 hours the solution is poured onto ice, and concentrated ammonia is added, and the mixture is extracted several times with methylene chloride. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on a silica gel column using toluene/ethyl acetate=8/2 as eluant.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])#[N:19]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]#[N:19])(=[O:28])=[O:27])[N:3]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: Brc1n[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1S(=O)(=O)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-bromo-1H-indazole (200 mg, 1.02 mmol) in 2 ml CH2Cl2 was added triethylamine (308 mg, 3.05 mmol) and 2-cyanobenzene-1-sulfonyl chloride (205 mg, 1.02 mmol). The reaction mixture was stirred overnight at room temperature. After completion the reaction mixture was concentrated under reduced pressure and the product was purified on SiO2 using 0% to 50% ethyl acetate in heptane as the eluent to give 3-bromo-1-(2-cyanophenylsulfonyl)-1H-indazole (360 mg) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:40][C:37]([Si:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5]2)([CH3:38])[CH3:39]
Reactant: COC(=O)c1cccc2cc(O)ccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-1-naphthalenecarboxylic acid, methyl ester (1.01 g, 5 mmol), triethylamine (1.55 mL, 6 mmol) and N,N-dimethyl-4-pyridineamine (0.30 g, 2.5 mmol) in CH2Cl2 (25 mL) is treated with a solution of chloro(1,1-dimethylethyl)diphenylsilane (1.55 mL, 6 mmol) in CH2Cl2 (10 mL) and stirred at room temperature overnight. The mixture is washed with saturated aqueous NaHCO3, dried (Na2SO4) and solvent is evaporated off under reduced pressure to give a residue, which is purified by column chromatography (SiO2; hexane/CH2Cl2 1:1) to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1COCC1.[Pd]>[CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)O)OC1CCCCO1
Reaction time: 3 h

Procedure:
(1.O.h) 430 mg of benzyl (2S 3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate in 10 ml of THF are treated with Pd/C 10% and hydrogenated for 3 hours. The catalyst is filtered off and, after evaporation of the filtrate, the crude product is chromatographed on silica gel. There is obtained (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H -pyran-2-yl)oxy]hexadecanoic acid.