Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([OH:37])[CH:33]=4)[CH:28]=3)=[N:25][N:26]=2)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:10]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([O:37][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:33]=4)[CH:28]=3)=[N:25][N:26]=2)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Reactant: CCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCC(=O)Oc1ccc2cc(-c3nnc(-c4ccc(CCCCCC)cc4)s3)ccc2c1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
In a 30 ml-round-bottomed flask, 0.30 g (0.77 mM) of 2-(4-hexylphenyl)-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole was dissolved in 5 ml of pyridine. To the solution, 0.20 ml (1.29 mM) of heptanoyl chloride was added dropwise under cooling with an iced water bath and stirring. After the addition, the iced water bath was removed. Then, the mixture was stirred for 7 hours at room temperature and left standing overnight at room temperature. The resultant mixture was poured into 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in toluene under heating, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene-acetone) to obtain 0.27 g of 2-(4-hexylphenyl)-5-(6-heptanoyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 69.8%) ##STR39##
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[C:3]1=[O:31].C1OCCOCCOCCOCCOCCOC1.[F-].[Cs+]>C(#N)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[C:3]1=[O:31]
Reactant: CN1CCC[C@@H](NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CN1CCC[C@@H](NC(=O)c2c[nH]c3ncc(C4CC4)nc23)C1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-oxo-piperidin-3-yl)-amide (145 mg, 0.33 mmol) in acetonitrile (14.2 mL) at room temperature was added 18-crown-6 (86.4 mg, 0.33 mmol) and cesium fluoride (497 mg, 3.27 mmol). The reaction mixture was heated to reflux temperature for 48 h then cooled to room temperature and filtered over a pad of celite. The filtrate was evaporated under vacuum and the crude residue was partitioned between EtOAc (25 mL) and water (25 mL). The organic extract was dried (Na2SO4) and evaporated under vacuum. The crude residue was purified by SiO2 column chromatography (25 g, CH2Cl2/MeOH/NH4OH, 100:0:0 to 90:9.5:0.5) to give 60 mg (59%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-oxo-piperidin-3-yl)-amide as a white solid. MS: (M+H)+=314.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([NH2:10])[CH2:9][CH2:8]1.[I:11][C:12]1[C:13]([CH3:23])=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:11][C:12]1[C:13]([CH3:23])=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([NH:10][C:7]1([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][CH2:8]1)=[O:18]
Reactant: NC1(c2ncccn2)CC1
Reactant: COc1cc(C)c(I)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(I)cc1C(=O)NC1(c2ncccn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(pyrimidin-2-yl)cyclopropanamine (2.00 g, 14.8 mmol) and 5-iodo-2-methoxy-4-methylbenzoic acid (4.75 g, 16.28 mmol) in DMF (8 ml) in a 25 ml RB flask was cooled to 0° C., and then added with N,N-diisopropylethylamine (12.92 ml, 74.0 mmol) followed by HATU (6.75 g, 17.76 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added ice water and extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with brine solution, dried over Na2SO4, filtered and concentrated. The crude product was purified by using a silica gel (60-120 mesh) column with 60% ethyl acetate in hexane as an eluent. Yield: 3.2 g, 48%. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=4.8 Hz, 2H), 8.52 (s, 1H), 8.47 (s, 1H), 7.03 (t, 1H, J=5.0 Hz), 4.02 (s, 3H), 2.63 (s, 3H), 1.83-1.80 (m, 2H), 1.52-1.49 (m, 2H). LCMS: (ES+) m/z=410 (M+H)+; Column—Ascentis Express C8 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH; Flow=1 ML/MIN; Time: 0.0, 1.5, 3.2; % A: 100.0, 0.0, 0.0; % B: 0.0, 100.0, 100.0; RT: 1.904 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=1[Cl:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[NH:15][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=1[Cl:26])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)c2ccccc2n1C
Reactant: CSc1ccc(Br)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc(SC)cc2Cl)c2ccccc2n1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
3-Amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.91 mmol) and 1-bromo-2-chloro-4-methylsulfanyl-benzene (304 mg, 1.28 mmol) were dissolved in toluene (5 ml) and Pd2(dba)3 (42 mg, 0.05 mmol) was added, followed by Xantphos (53 mg, 0.09 mmol) and potassium phosphate tribasic (386 mg, 1.82 mmol). The mixture was degassed and purged with argon, then stirred under argon at 120° C. for 16 hours. After cooling, the mixture was filtered through celite then concentrated. Purification of the resultant residue by flash chromatography (Si-PCC, ether:pentane gradient 1:4 to 1:0) gave the title compound as a yellow oil (300 mg, 88%). LCMS (method B): RT=2.64, M+H+ 376/378.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]=[CH:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[Li+].[F-].[CH2:26]([N:33]([CH2:39]OC)[CH2:34][Si](C)(C)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]3[CH2:34][N:33]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:39][CH:20]3[CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [F-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C1CN(Cc3ccccc3)CC1CC2
Reaction time: 6 h

Procedure:
4-Oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.92 g, 9.15 mmol), LiF (296 mg, 11.4 mmol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine are mixed together in CH3CN (10 ml). The reaction mixture is sonicated under N2. The water bath is kept under 35° C. with ice. After 6 h, solvents are removed in vacuo. The residue is put on a column (1:1 EtOAc hexanes) to afford the title compound as clear oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 1.56 (9H, s), 1.88-2.00 (2H, m), 2.65 (1H, m), 2.92-3.02 (4H, m), 3.24 (1H, m), 3.50-3.59 (3H, m), 4.06 (1H, q), 4.19 (2H, q), 7.18-7.27 (5H, m), 7.62 (1H, s). MS (ES+) 453 (M+1) Step 2: 6-Benzyl4-oxo-4,4a,5,6,7,7a,8,9-octahydro-1H-1,6-diaza-cyclopenta[f]azulene-3-carboxylic acid pyridin-2-ylamide
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Reactant: CCCCNc1ccc(CCN)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCNc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Triethylamine (0.28 g, 2.77 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (0.30 g, 1.40 mmol) in toluene (10 ml). The mixture was stirred at room temperature. Then, 4-butylaminophenethylamine (0.40 g 2.08 mmol) was added after stirring for 3 hours, water (20 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-butylaminophenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.30 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Product: CSc1ccc(Cl)c(C(=O)Cl)c1

Procedure:
A mixture of 2.03 g of 2-chloro-5-(methylthio)benzoic acid and 10 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are removed under vacuum and 20 ml of toluene added and removed under vacuum (2 times) to give 2.2 g of brown needles.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:20])=[CH:17]\[CH:18]=[O:19].C[OH:23]>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:20])=[CH:17]\[C:18]([OH:23])=[O:19]
Reactant: CO
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C=O)C(C)(C)CCC1
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A mixture was formed of 2.42 g (27.89 mmol) of MnO2, 0.35 g (7.2 mmol) of NaCN, 0.12 ml (2.1 mmol) glacial acetic acid in 20 ml of CH3OH at 0° C. A separate solution was formed of 600 mg (2.1 mmol) of 9-cis-retinal (I) in 9 ml of CH3OH, also at 0° C. The solution of 9-cis-retinal was added dropwise to the mixture and stirred for 2.5 h at constant temperature and the reaction mixture was filtered through Celite. The filter cake was washed with a 1:1 mixture of CH3OH and water. The filtrates were combined and diluted with additional water and then extracted three times with ether. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Purification by silica gel flash column chromatography using 20:1 hexane:ethyl acetate as eluent gave the pure methyl ester of 9-cis-retinoic acid (II) in the amount of 530 mg, a yield of 80%. The structure was confirmed by NMR. ##STR9##
Reaction SMILES: O=[C:2]([OH:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:12]=[CH:13][C@@H]([C@H]([C@@H](CO)O)O)O>>[O:12]=[CH:13][C@@H:2]([C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4])[OH:11]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
When the P. ananatis NA1 strain was cultured with the mixed carbon source of glucose and xylose (MSII-GX medium), the glutamic acid yield was 25.7% (Table 2). In this case, accumulation of xylonic acid was observed, and thus it was suggested that most of xylose was converted into xylonic acid. It is estimated that the accumulation of xylonic acid with the P. ananatis NA1 strain was provided by the activity of glucose dehydrogenase of P. ananatis.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1>>[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:26])=[CH:20][CH:19]=1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on a silica gel column using ethyl acetate/methanol =9:1 as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Rh]>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Agent: [Rh]
Solvent: CCO
Product: CC(=O)NC(C)CCC1CCC(O)CC1

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (1.0 g, 4.82 mmol) were dissolved in 100 ml of ethanol and hydrogenated in the presence of 5% rhodium on carbon (695 mg) at 100° C. and 100 bar hydrogen pressure for 18 h. The catalyst was filtered off and the filtrate was concentrated. Yield: 1.06 g of crude product, M+H+: 214.2.
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24].[Cl-].[Mn+2:47].[Cl-].C(O)C>O>[Mn:47].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24]
Reactant: [Mn+2]
Agent: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H]1O[C@@H](CC(=O)OO)[C@H](C)C[C@@H]1C)[C@H]1O[C@](C)([C@]2(O)O[C@](CC)([C@@H](O)CC)C[C@H]2C)C[C@@H]1C
Agent: [Cl-]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: [Mn]
Reaction time: 18 h

Procedure:
A mixture of 6.5 g sodium lysocellin, 2.0 g manganese chloride and 100 ml of 90% ethanol was stirred and held at ambient temperature for 18 hours. Stirring was continued and water added slowly to precipitate a tacky semi-solid. Removal of the mother liquor by decantation and trituration of the residue with fresh water gave a filterable amorphous solid which was isolated and dried (6.4 g). The product had a melting point of 112.8° C. Analysis: Calculated % Mn (4.19); Found (3.75).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.[CH2:21]([O:23][C:24](=[O:32])[CH:25](Cl)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH3:22]>O>[CH2:21]([O:23][C:24]([CH:25]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:9]([F:19])([F:20])[F:8])=[CH:11][CH:12]=1)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:32])[CH3:22]
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(=O)c1ccc(C(F)(F)F)cc1)C(=O)C(C)C
Temperature: 90 °C

Procedure:
Sodium Hydride, 60% mineral oil (1.9 g, 46.3 mmol) and dimethylformamide (50 mL) are stirred at room temperature and 4-(trifluoromethyl)benzoic acid (8.0 g, 42.1 mmol) is added. To the resulting slurry is added 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (8.5 g, 44.2 mmol) and the resulting mixture is heated to 90° C. for 3 hr. The reaction mixture is cooled, diluted with water (100 mL), and product is extracted with ethyl acetate (100 mL). The organic layer is washed with water (three 100 mL portions) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to constant weight to give 4-trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butyl ester as a colorless oil, 14.6 g, 100%. The resulting oil is stirred in a mixture of acetic acid (100 mL) and ammonium acetate (9.75 g, 126.5 mmol) at reflux 1 hr, then 20 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between aqueous saturated sodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL. The layers are separated, the aqueous layer is washed with ethyl acetate (100 mL). The organic extracts are combined, washed with water and brine (100 mL each) dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is purified over silica eluting with 9:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester as a white solid, 8.1 g, 60%. MS (M++1) 328.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:34]=[C:29]([NH:28][S:25]([CH3:24])(=[O:26])=[O:27])[CH:30]=[CH:31][CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(NS(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-(Methanesulfonylamino)phenylboronic acid (ABCR, Karlsruhe, Germany, 28 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=463 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.88 (s, 1H), 8.97 (s, 1H), 8.12-8.10 (m, 2H), 7.82-7.79 (m, 1H), 7.56-7.54 (m, 1H), 7.45-7.41 (m, 1H), 7.36-7.34 (m, 1H), 7.21-7.16 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 3.03 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=1
Reactant: Brc1ccccn1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
6.93 g (29.9 mmol) of 4-bromobenzaldehyde dimethyl acetal in 40 ml of THF are added dropwise to a warm (from 40° C. to 50° C.) suspension of 0.8 g (31.6 mmol) of magnesium turnings and a small amount of iodine in 10 ml of THF. The reaction mixture is heated to 65° C. and stirred at that temperature for about 30 min. The mixture is allowed to cool to room temperature and the Grignard reagent is added dropwise to a solution of 4.46 g (28.2 mmol) of 2-bromopyridine (Fluka, Buchs, Switzerland) and 0.4 g (0.74 mmol) of DPPP (Fluka, Buchs, Switzerland) in 100 ml of THF (slightly exothermic reaction). After the dropwise addition is complete, the reaction mixture is boiled under reflux for 4 hours and is then allowed to cool; 100 ml of water are added. The mixture is concentrated to about 50 ml using a rotary evaporator, diluted with ethyl acetate and extracted with 0.1N hydrochloric acid (3×). The combined HCl extracts are stirred at room temperature for 20 min, rendered basic with concentrated ammonia solution and extracted with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel (hexane/ethyl acetate 2:1). The product-containing fractions are concentrated, with the desired title compound crystallising out spontaneously. TLC: Rf =0.22 (hexane/ethyl acetate 2:1). HPLC20-100 : tRet =6.08. 1H-NMR (CDCl3 ; 200 MHz): 8.73/d, J=5 (2H); 8.16 and 7.97/each d (2×2H); 7.80/d, J=4 (2H); 7.3/m (1H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([O:26][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OC(=O)N(C)C)ccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
Dimethylcarbamoyl chloride (0.2 mL, 2.17 mmol) was added dropwise to a stirred solution of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (199 mg, 0.47 mmol), 4-dimethylaminopyridine (DMAP) (20 mg), and triethylamine (0.8 mL, 5.74 mmol) in anhydrous DCM (15 mL) at 0° C. under nitrogen, and the resulting mixture was stirred at 50° C. for 5 hours. The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel eluting with DCM-20%MeOH/DCM (90:10) to give the title compound (171 mg, 74%); 1H-NMR (CDCl3): δ 10.62 (1H, s), 7.78 (s, 1H), 7.74 (1H, d), 7.63-7.59 (2H, m), 7.16-7.10 (3H, m), 6.84 (1H, dd), 4.24 (2H, q), 4.08 (2H, br s), 3.14 (3H, s), 3.03 (3H, s), 1.59 (6H, s), 1.23 (3H, t); MS (ES): 494 (MH+).
Reaction SMILES: C([O:9][C@H:10]([CH3:31])[C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[C@H:13]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@@H:12]1[OH:30])(=O)C1C=CC=CC=1.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C.CCOC(C)=O.N>[CH3:29][O:28][CH2:27][CH2:26][O:25][C@@H:13]1[C@H:12]([O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:11]([C@@H:10]([CH3:31])[OH:9])[O:15][C@H:14]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCO[C@@H]1[C@H](O)[C@@H]([C@@H](C)OC(=O)c2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: N
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCO[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@@H](C)O)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A mixture of Compound 10 (1.33 g, 3.06 mmol) and imidazole (2.09, 30.70 mmol) was dissolved in anhydrous DMF (11.4 mL). To this solution tert-butyldimethylsilyl chloride (2.31 g, 15.33 mmol) was added with stirring at room temperature for 16 h under an atmosphere of argon. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous NaHCO3 (2×60 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was dissolved in methanolic ammonia (20 mL, 7 M) and stirred for 24 h at 55° C. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography and eluted with 50% EtOAc in hexanes to yield Compound 11 (1.21 g, 89%). ES MS m/z 455.2 [M+H]+.