Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2cccnc2)c1
Yield: 72.7 %

Procedure:
1-fluoro-3-nitrobenzene (1 g, 7 mmol, 1 eq), 3-hydroxypyridine (674 mg, 7.09 mmol, 1.00 eq), K2CO3 (1.18 g, 8.54 mmol, 1.20 eq) and DMF (10 mL) were added to a microwave vial and microwaved at 200° C. for 30 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 1.1 g (72%) of the title compound as a brown oil: 1H NMR (400 MHz, DMSO-d6) 8.49 (d, J=2.8 Hz, 1H), 8.46 (d, J=4.6 Hz, 1H), 8.02 (dd, J=8.2, 2.0 Hz, 1H), 7.78 (t, J=2.3 Hz, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.54 (dd, J=8.3, 2.4 Hz, 1H), 7.49 (dd, J=8.4, 4.6 Hz, 1H); ES-MS [M+1]+: 217.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:34])[N:22]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:24]=[C:23]([NH2:34])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(-c5ccc(F)cc5)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
180 mg (0.70 mmol) of {3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}amine (from example XLII) and 191 mg (0.73 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX) are suspended in 10 ml of water. 101 μl of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline using saturated sodium carbonate solution and extracted three times with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[OH:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>[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.CCN(CC)CC>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]#[C:30][C:29]([OH:28])([CH3:33])[CH3:32])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C#CC(C)(C)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Yield: 88.6 %

Procedure:
A microwave vial was charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (216 mg, 0.50 mmol), 3-hydroxy-3-methyl-1-butyne (0.24 mL, 2.50 mmol), CuI (9.5 mg, 0.05 mmol) and Et3N (4 mL). The mixture was sparged with N2 for 5 min and PdCl2(PPh3)2 (21 mg, 0.03 mmol) was added. The mixture was sparged with N2 for 5 min and heated at 100° C. for 2 h in the microwave. The mixture was diluted with EtOAc (200 mL), washed with 5% aq HCl (2×30 mL), satd aq NaHCO3 (30 mL) and brine (30 mL), and dried over Na2SO4. Removal of the solvent left a dark oil (379 mg) which was applied to a 2 g silica SPE Cartridge. The cartridge was eluted with 0, 25, 50 and 75% EtOAc in hexanes (20 mL) of each and EtOAc (2×20 mL) to give six fractions. Fractions 4 and 5 were pooled and concentrated to afford the title compound (193 mg, 89%) as an oil. LC-MS Method 1 tR=1.53 min, m/z=436, 378; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 1.60 (s, 6H), 2.15 (m, 1H), 2.19 (s, 2H), 2.20-2.45 (2H), 2.80 (m, 1H), 5.66 (q, 1H), 6.86 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=1)[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1)[CH3:2]
Reactant: CCCC(=O)C(=CNc1cccc(CO)c1)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1cccc(COC(=O)c2ccccc2)c1)C(=O)OCC
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a stirred and cooled (ice-bath) solution of ethyl-2-butyryl-3-(3-hydroxymethylphenylamino)acrylate (29.13 g, 0.1 mol) in pyridine was added dropwise benzoyl chloride (21.09 g, 0.15 mol). The ice bath was removed and the mixture stood for 16 hours, then evaporated, treated with chloroform (200 ml) and washed with saturated aqueous sodium bicarbonate (200 ml), water (200 ml), and 2N hydrochloric acid (2×150 ml). After drying (Na2SO4) and stirring with charcoal, the solution was filtered and evaporated to an oil, which crystallised slowly under petroleum ether (b.p. 40-60) to give the title compound (34.5 g) m.p. 59°-63°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].Cl>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethylsulfoxide (8 mL) was heated at 90° C. for 30 minutes under a nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzonitrile (1.806 g, 0.0099 mol) in dimethylsulfoxide (8 mL) was added dropwise over a 30 minute period at 90°, then let the reaction stir for 1 hour at the same temperature. The reaction was then cooled in an ice bath and poured into 30 mL of ice-water. The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with ethyl ether (3×100 mL). The combined ethereal extracts were washed with water (3×150 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification by silica gel chromatography using 4% ethyl acetate/methylene chloride as eluent provided the product as an orange solid (0.984 g, 39%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15].[Cl-].[S:17](=[CH2:20])(=[O:19])=[O:18]>N1C(C)=CC=CC=1C.CCOCC>[CH3:20][S:17]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:13])([F:14])[C:10]1=[O:15])(=[O:19])=[O:18]
Reactant: O=C1N(c2ccccc2CO)CC1(F)F
Reactant: C=S(=O)=O
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: CS(=O)(=O)OCc1ccccc1N1CC(F)(F)C1=O
Temperature: 7 °C
Reaction time: 1.5 h

Procedure:
0.17 mmole of compound 4a is dissolved in 0.8 ml of 2,6-lutidine at 0° C., followed by the addition of 0.18 mmole of sulphonyl methane chloride to said solution. After stirring the reaction mixture for 90 min. at a temperature of 4 to 10° C., the solution is taken up in 1 ml of ether and then washed twice with 0.5 ml of saturated aqueous NaCl solution.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:38](=O)[N:39]([CH2:41][CH2:42][NH2:43])C)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[CH:27][C:28]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:43][CH2:42][CH2:41][NH:39][CH3:38])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3c(OC)cccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with TFA and neutralisation, the title compound.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][S-:15].[Na+]>CN(C)C=O>[CH3:14][S:15][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(SC)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)cc1SC
Temperature: 50 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
A mixture of methyl 2-fluoro-4-methylsulphenylbenzoate (4.1 g), sodium thiomethoxide (1.48 g) and N,N-dimethylformamide (16 ml) was stirred at 50° C. for 18 hours, poured onto water and extracted (ethyl acetate). The extract was washed (water), dried (magnesium sulphate) and evaporated to give methyl 2-methylsulphenyl-4-methylsulphenylbenzoate (2.09 g) as an orange oil, NMR (CDCl3) 2.0 (s,3H), 2.4 (s,3H), 3.65 (s,2H), 3.9 (s,3H), 7.05 (dd,1H), 7.15 (d,1H), 7.9 (d,1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH:31]3[CH3:34])=[CH:26][CH:25]=2)=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)=[CH:25][CH:26]=4)[CH:31]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ncc(-c2ccc3c(c2)C(C)NCC3)c(OC)n1
Product: COc1ncc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Br)cn4n2)CC3)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[C:19]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]3[C:19]4[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1

Procedure:
Prepared according to Procedure A from 4-benzenesulphonylaniline (Helv. Chim. Acta., 1983, 66 (4), 1046) and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.09 (1H, s), 8.80-8.88 (2H, m), 8.19 (2H, d), 7.94-8.09 (4H, m), 7.53-7.20 (3H, m); m/z (M+1)+397.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=1[CH3:19].O>O1CCCC1>[F:1][CH:2]([F:5])[CH2:3][O:4][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=1[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])c(N)nc1Cl
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(N)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
2,2-Difluoro ethanol (418 mg, 5.1 mmol) was dissolved in tetrahydrofuran (15 ml), sodium hydride (60%) (180 mg, 4.5 mmol) was added thereto under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 6-chloro-5-methyl-3-nitro-2-pyridineamine (600 mg, 3.20 mmol) in tetrahydrofuran (15 ml) was dropped, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate, and after washed with sodium bicarbonate solution, dried over magnesium sulfate. The residue obtained by evaporating the solvent was triturated with n-hexane to yield the title compound (685 mg, 3.1 mmol, 96%) as an orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH:22]=4)[C:20]#[N:21])[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:20]([C:19]1[CH:22]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][N:1]4[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:14]=2)[CH:16]=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])#[N:21]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 80 °C
Yield: 41.4 %

Procedure:
A mixture of 5-[3-(1H-indol-4-yl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D49) (100 mg, 0.29 mmol), ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and cesium carbonate (189 mg, 0.58 mmol) in DMF (2 ml) was heated at 80° C. for 1 hour. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and heated overnight at 80° C. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and cesium carbonate (189 mg, 0.58 mmol) and heated for 24 hours. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and heated for 24 hours. Added ethyl 4-bromobutyrate (85 mg, 0.44 mmol) and heated for 6 hours. Added EtOAc (20 ml) and washed with water (20 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ethanol to give the title compound (55 mg) as a white solid. MS (ES) C26H26N4O4 requires 458; found 459 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH:32]=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH:33]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
Product: CCOC(=O)c1ccc(C2=CCCc3ccccc32)cc1
Yield: 93.5 %

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (2.58 g, 5.88 mmol) and 3,4-dihydro-naphthalen-1-yl trifluoromethanesulfonate (1.80 g, 6.47 mmol) were reacted in the manner of Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 10% ethyl acetate in hexane followed by recrystallization from pentane (−20° C.) afforded the title compound (1.53 g) as slightly yellow crystals, m.p. 81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in example 5D, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one and piperidine (with no additional sodium iodide) gave the title compound as white powder. MS: 452.2 (MH+, 2Cl).
Reaction SMILES: C([Li])(C)(C)C.F[B-](F)(F)F.[CH:11]([S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12]>CCCCC.O1CCCC1>[C:21]1([S:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([CH3:13])[CH3:12])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[S+](c1ccccc1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)=S(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2 ml of a solution of 1.6M of tert.-butyllithium in pentane were added dropwise at -70° C. under an inert atmosphere to a stirred mixture of 950 mg of the tetrafluoroborate of isopropyldiphenylsulfonium in 15 ml of tetrahydrofuran and the mixture was stirred at -70° C. for 30 minutes to obtain a solution of diphenylisopropylidene sulfurane. The said solution at -70° C. was added slowly with stirring under an inert atmosphere to a mixture of 350 mg of 5(RS)methoxy-2,5-dihydrofuran-2-one [prepared by method of Schroeter et al, Liebigs Ann. Chem., Vol. 697 (1966), p. 42] and 15 ml of tetrahydrofuran cooled to -90° C. and the mixture was allowed to stand at -78° C. for one hour and then at -50° C. for another hour. The mixture was poured into an aqueous monosodium phosphate solution and the mixture was extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 1-1 ether-petroleum ether mixture yielded 480 mg of diphenyl sulfide, 260 mg of (1RS,5SR)6,6-dimethyl-4(RS)-methoxy-3-oxabicyclo[3,1,0]hexan-2-one and 100 mg of unreacted lactone.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[C:5]2[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:4]=2[O:3]1.O1CCCC1.[H][H]>CO.[C].[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:18]=[CH:19][C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:4]=3[O:3][C:2]([CH3:1])([CH3:27])[C:7]2=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2cccc([N+](=O)[O-])c2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2cccc(N)c2)C1=O

Procedure:
To a solution of N-[2,2-dimethyl-4-(3-nitrophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 146; 240 mg) in methanol (5 mL)-tetrahydrofuran (5 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give N-[4-(3-aminophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-methanesulfonamide as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23]Br)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Yield: 121.9 %

Procedure:
A mixture of 1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 8.3 g of potassium carbonate and 50 ml of butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave 6.0 g of pure 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde.
Reaction SMILES: OCCC1C=C(C=CC=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:39][CH2:38][CH2:37][CH2:36][C:13]=2[C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:16])=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)O[C:54](=O)[C:53]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]1=2)=O>>[CH3:20][CH2:19][CH:18]([NH:17][CH2:15][CH2:54][C:53]1[CH:48]=[C:49]([CH:50]=[CH:51][CH:52]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:39][CH2:38][CH2:37][CH2:36][C:13]=2[C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=2)=[CH:22][CH:23]=1)=[O:16])=[O:8])[CH2:23][CH3:22]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCO)c4)sc4c3CCCC4)cc2)cc1
Product: CCC(CC)NCCc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Yield: 185.9 %

Procedure:
By using 250 mg of methyl 4-[2-(4-{[(2-{[3-(2-hydroxyethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 450 mg of Dess-Martin Periodinane, the reaction similar to Preparation Example 2 was performed, and then the reaction similar to Preparation Example 14 was performed, thereby obtaining 260 mg of methyl 4-{2-[4-({[2-({3-[2-(pentan-3-ylamino)ethyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.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>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:17]=4[NH:16][C:15](=[O:18])[CH2:14]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1cccc(Nc2cccc3c2NC(=O)C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 7-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (80 mg, 0.33 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (113 mg, 0.37 mmol), N,N-diisopropylethylamine (0.22 g, 1.67 mmol) and HATU (0.14 g, 0.37 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).