Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]([C:17]1[N:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16].C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.NC1C=CC(N2CCNCC2)=CC=1F.[CH2:64]([O:71][C:72]([C@H:74]1[CH2:78][CH2:77][CH2:76][C@@H:75]1[C:79](O)=[O:80])=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:64]([O:71][C:72]([C@H:74]1[CH2:78][CH2:77][CH2:76][C@@H:75]1[C:79]([N:11]1[CH2:10][CH2:9][N:8]([C:6]2[CH:5]=[CH:4][C:3]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[C:2]([F:1])[CH:7]=2)[CH2:13][CH2:12]1)=[O:80])=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: O=C(O)[C@H]1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1F)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccc(N2CCNCC2)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCN(C(=O)[C@H]3CCC[C@@H]3C(=O)OCc3ccccc3)CC2)cc1F)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2-fluoro-4-piperazin-1-yl-phenyl)-amide (0.22 g, 0.5 mmol) prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 4-(4-amino-3-fluoro-phenyl)-piperazine using a procedure similar to the one described above, (1S,2S)-cyclopentane-1,2-dicarboxylic acid monobenzyl ester (0.26 g, 0.5 mmol), N-hydroxybenzotriazole (0.1 g, 0.74 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.74 mmol), N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous dichloromethane (4 mL) was stirred at room temperature for overnight. After the reaction, solvent was evaporated. The resulted mixture was mixed with water and extracted with ethyl acetate twice. The organic layers were collected, combined, washed with brine before dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by reverse phase HPLC (10%-80% acetonitrile in water) to gave (1S,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl ester as a yellow solid. LCMS calcd for C35H32F4N4O5 (m/e) 664, obsd 665 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16].S(Cl)(Cl)=O.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:14]([NH:17][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Br:1])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 20 h

Procedure:
5 g of 2-bromo-4-nitrobenzoic acid is converted into acid chloride, which is dissolved in 50 ml of tetrahydrofuran and added in drops to 3 ml of allylamine in 20 ml of tetrahydro-furan, by 2 hours of boiling with 30 ml of thionyl chloride and distilling-off of excess thionyl chloride. After 20 hours at room temperature, it is dispersed between 1N hydrochloric acid and ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized with hexane. 5.6 g of 2-bromo-4-nitrobenzoic acid-allylamide, melting point 98-100° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:18]([CH3:32])=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1.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>[CH3:32][C:18]1[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[N:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:16][CH:17]=1
Reactant: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Cc1cccc(C(F)(F)F)c1
Yield: 51.9 %

Procedure:
A stirred mixture of 4-(trifluoromethyl)benzene boronic acid (430 mg, 2.3 mmol), the title compound of Step A (500 mg, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (120 mg, 0.17 mmol) and sodium carbonate (550 mg, 5.2 mmol) in a mixture of 6 mL of water and 2 mL of tetrahydrofuran was heated at reflux for 1.5 h. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (20 to 25% ethyl acetate in hexane) followed by trituration with 10% diethyl ether in hexane afforded 350 mg of the title compound of Step B, a compound of this invention, as a yellow-tinted solid melting at 112-113° C. 1H NMR (CDCl3): δ8.55 (m, 3H), 7.70 (d, 2H), 7.60 (s, 1H), 7.55-7.40 (m, 3H), 4.25 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:17])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>>[C:5]([Cl:3])(=[O:17])[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: C=CCCCCCCC=CC(=O)Cl
Yield: 88 %

Procedure:
Thionyl chloride (25.6 ml, 0.36 mole) was added to undec-10-enoic acid (62.6 grams, 0.34 mole) over a period of 45 minutes, while stirring and the resulting mixture was thereafter refluxed for 2 hours. The acyl chloride was then removed under reduced pressure (102° C./2 mm Hg), to give Compound 55 (see, Scheme 30 below) in 88% yield.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O>Cl.O.[Zn]>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[OH:1]
Reactant: COc1ccc2c(c1O)CCC2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Product: COc1ccc2c(c1O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
The 20.5 g of 2,3-dihydro4-hydroxy-5-methoxy-1H-inden-1-one were suspended in a mixture of 310 ml of concentrated aqueous hydrochloric acid and 53 ml of water. Freshly prepared zinc amalgame (from 87 g of zinc wool) was added and the mixture was stirred for 3 hours at ambient temperature. After decantation the resting zinc amalgame was washed three times with diethyl ether and the acidic water solution was extracted with diethyl ether. The combined ether solutions were washed with a 1N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated in vacuo to afford 15.0 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol, M.S. (C.I.) (M/Z): 165 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[C:24]([C:23]1[CH:22]=[N:21][N:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH2:30]3)[C:6]=12)#[N:25]
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(C(=O)OCc3ccccc3)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 48.6 %

Procedure:
A mixture of 6.3 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 4.2 g of 1-piperazinecarboxylic acid, phenylmethyl ester and 4.1 g of triethylamine in 250 ml of tetrahydrofuran was stirred under reflux for 18 hours, then cooled and filtered. The filtrate was evaporated, the residue taken up in chloroform, washed with water, dried, filtered and concentrated. The residual oil was triturated three times with ether:hexane (1:1), then with hexane. The solid was collected, washed with hexane and dried. The solid was heated to solution in 25 ml of ethyl acetate, filtered, diluted with 25 ml of hexane and cooled, giving 4.6 g of the desired product, mp 113°-115° C.
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([C:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH:28]=4)=[N:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH3:38]>C(O)C>[F:39][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([CH:27]4[CH2:28][CH2:29][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]4)=[N:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH3:38]
Reactant: CCOC(=O)C1CC=C(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn2)CC1
Solvent: CCO
Product: CCOC(=O)C1CCC(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn2)CC1
Yield: 100.2 %

Procedure:
A solution of Example 163 (˜0.05M, 545 mg, 1.01 mmol) in ethanol was hydrogenated using an H-Cube® (ThalesNano) at a flow rate of 0.5 mL/minute, in full H2 mode (1 bar) at 50° C. Removal of the ethanol under vacuum gave the title compound (545 mg, 89%) as a pale brown foam consisting of a pair diastereosiomers in a 3:1 ratio. δH (300 MHz, CD3OD) 8.76 (s, 2H), 8.24 (d, J 7.4 Hz, 1H), 7.25 (m, 2H), 7.07 (m, 3H), 6.81 (t, J 74.1 Hz, 1H), 4.32 (s, 2H), 4.09 (2H, qd, J 7.3, 1.2 Hz), 2.97 (m, 1H), 2.64 (m, 1H), 2.33 (m, 1H), 1.83 (m, 8H), 1.21 (t, J 7.1 Hz, 3H). LC-MS (pH 3): MH+ m/z 539.8, RT 2.46 minutes; 539.8, RT 2.51 minutes. LC-MS (pH 10): MH+ m/z 539.8, RT 2.47 minutes; 539.8, RT 2.51 minutes.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:31][C:32]1[CH:33]=[CH:34][C:35]2[CH:39]=[C:38]([S:40]([N:43]3[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]3)(=[O:42])=[O:41])[S:37][C:36]=2[CH:50]=1.[Na+].[Cl-]>O1CCCC1.C(O)C.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:46]2[CH2:47][CH2:48][N:43]([S:40]([C:38]3[S:37][C:36]4[CH:50]=[C:32]([Cl:31])[CH:33]=[CH:34][C:35]=4[CH:39]=3)(=[O:41])=[O:42])[CH2:44][CH2:45]2)=[CH:27][CH:28]=1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cc2ccc(Cl)cc2s1)N1CCC(=Cc2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
In a mixed solvent of tetrahydrofuran (10 ml) and ethanol (10 ml) was dissolved 4-bromobenzyl triphenylphosphonium bromide (512 mg). The resulting solution was cooled to 0° C., followed by the successive addition of sodium hydride (60% in oil, 40 mg) and 1-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]piperidin-4-one (297 mg). The resulting mixture was stirred at room temperature for 16 hours and at 50° C. for 9 hours. Saturated aqueous NaCl solution and ethyl acetate were added to the reaction mixture to separate the same. The resulting organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated and the residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby the title compound (colorless powder, 133 mg) was obtained.
Reaction SMILES: [CH3:1][Co:2]([CH3:8])[C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[H][H]>>[Co:2].[CH3:1][Co:2]([CH3:8])[C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Agent: C[Co](C)C1=CC=CC1
Product: [Co]

Procedure:
Subsequently, the gas source 14d vaporizes bis-methyl-cyclopenta-dienyl-cobalt expressed by the chemical formula "Co(CH3C5H4)2 ", and the bis-methyl-cyclopenta-dienyl-cobalt gas is carried on hydrogen gas. The gaseous mixture is supplied to the chamber 14a. The hydrogen carrier gas is regulated 100 to 400 sccm, and the bis-methyl-cyclopenta-dienyl-cobalt gas is regulated to 10 to 40 sccm. The gaseous mixture is maintained at 13 to 52 Pa in the chamber, and the p-type silicon substrate 11 is heated to 200 to 400 degrees centigrade. Cobalt is produced from the bis-methyl-cyclopenta-dienyl-cobalt gas through the pyrolysis, and is deposited to 10 to 20 nanometers thick on the entire surface of the structure.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][CH:8]=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]2[O:12][C:19](=[O:20])[NH:14][N:13]=2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1ccc(OCCCC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]nc(-c2ccc(OCCCC(F)(F)F)cc2)o1

Procedure:
4.09 g of 4-(4,4,4-trifluorobutoxy)benzoic acid hydrazide, dissolved in 56 ml of hot toluene, are introduced into a 100 ml three-necked flask under nitrogen at room temperature. 12.1 ml of phosgene dissolved in toluene (1.93M) are then added dropwise. The mixture is heated to 100°-110° C. for 1 h 30 min and the excess phosgene is then stripped off using a stream of nitrogen. The reaction medium is cooled and the precipitate formed is filtered off and dried under vacuum. 4.4 g of product are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.6 g of 4-(4-acetamidophenylamino)-3-amino-5-sulfamoylbenzoic acid, 20 ml of water and the sufficient amount of N aqueous sodium hydroxide to reach a pH = 7.4, 1.3 g of benzyl chloride are added while stirring at 30°. The mixture is stirred for 16 hours at room temperature, during which time 4N aqueous sodium hydroxide is added dropwise to keep said pH value. It is filtered, the filtrate acidified with 2 ml of glacial acetic acid and the precipitate formed filtered off, to yield the 4-(4-acetamidophenylamino)-3-benzylamino-5-sulfamoylbenzoic acid which is used as such without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[CH:31]=[C:30]([CH3:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: Cc1cc(Cl)nc2ccccc12
Product: COc1ccc(C(=O)N2CC3CN(c4cc(C)c5ccccc5n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-4-methyl-quinoline. MS (ESI) mass calcd. for C25H27N3O3, 417.51; m/z found, 418.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.S(O[CH2:56][CH:57]1[CH2:62][CH2:61][N:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][CH2:58]1)(C1C=CC(C)=CC=1)(=O)=O.FC1C=CC(CBr)=CC=1>>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:56][CH:57]1[CH2:62][CH2:61][N:60]([C:63]([O:65][C:66]([CH3:67])([CH3:69])[CH3:68])=[O:64])[CH2:59][CH2:58]1)[C:12]4=[O:20]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: Fc1ccc(CBr)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)C(C)(C)CO5)c3ccccc32)CC1
Yield: 70 %

Procedure:
Following the procedure as described in EXAMPLE 10, and making non-critical variations using 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 4-fluorobenzyl bromide, the title compound was obtained in 70% yield: mp 65-75° C.; 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.18 (d, 1H), 7.05 (t, 1H), 6.89 (d, 1H), 6.38 (s, 1H), 6.28 (s, 1H), 4.88 (d, 1H), 4.64 (d, 1H), 4.18 (s, 2H), 4.17-4.01 (br, 2H), 3.74-3.53 (m, 2H), 2.74-2.59 (m, 2H), 2.11-1.92 (m, 1H), 1.70-1.59 (m, 2H), 1.43 (s, 9H), 1.37-1.19 (m, 2H), 1.17 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 161.3, 161.0, 154.7, 142.8, 132.6, 129.9, 128.7, 124.2, 123.3, 120.3, 116.2, 108.5, 93.4, 85.4, 80.6, 79.5, 57.7, 45.7, 41.3, 35.0, 30.0, 28.4, 27.8, 27.5; MS (ES+) m/z 527.5 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Cl:24][C:25]1[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C.[Cu](I)I>[Cl:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Fc1ncccc1Cl
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncccc4Cl)cc3n2C)c1
Yield: 58 %

Procedure:
A solution of methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10 mmol), 3-chloro-2-fluoropyridine (1.45 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol) and cesium carbonate (9.77 g, 30 mmol) in DMF (50 mL) was stirred in a nitrogen atmosphere at 80° C. for two hours. After leaving to cool, a saturated ammonium chloride aqueous solution (200 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL). Then, the organic layer was washed with water (200 mL) twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (methylene chloride/methanol, 95:5) to obtain the title compound (2.46 g, 58%) as a white solid.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][N:15]=[C:16]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CC1C=CC(Cl)=CC=1Cl>C(=O)(O)[O-].[Na+]>[CH3:13][O:14][N:15]=[C:16]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: CON=C(c1ccccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: CON=C(c1ccccc1O)n1ccnc1
Yield: 78.5 %

Procedure:
Dry anisole (6 ml) and aluminium chloride (0.59 g) were added to 2-(2,4-dichlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.75 g), and the mixture was stirred under ice-cooling for 2 hours. After completion of the reaction, a half-saturated aqueous solution of sodium bicarbonate (100 ml) was added slowly, and the mixture was extracted with ether (50 ml) and ethyl acetate (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give 2-hydroxy-α-(1-imidazolyl)benzaldehyde O-methyloxime (0.34 g) as colorless crystals. mp. 103.5°-104.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:15]=[N+:16]([O-])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH:21]=1)#[N:2].C(OC(=O)C)(=[O:24])C>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[C:15](=[O:24])[NH:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH:21]=1)#[N:2]
Reactant: CC1(C)CC(c2ccc[n+]([O-])c2)c2cc(C#N)ccc2O1
Reactant: CC(=O)OC(C)=O
Product: CC1(C)CC(c2ccc[nH]c2=O)c2cc(C#N)ccc2O1
Reaction time: 0.5 h

Procedure:
400 mg of 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide were dissolved in 10 ml of acetic anhydride and heated at reflux for 8 hours. After removal of the solvent by evaporation the residue was dissolved in ethanol and 15 mg of 80% (w/w) sodium hydride were added. After stirring for 30 minutes the mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The aqueous phase was acidified with dilute hydrochloric acid, extracted with ethyl acetate, then made basic with sodium bicarbonate solution and re-extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 8% (v/v) methanol/ethyl acetate for the elution to give 310 mg of 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-2(1H)-pyridone of melting point 196°-197° C. after recrystallization from t-butyl methyl ether.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:18][C:19]([CH3:22])=[N:20][N:21]=1)(C)(C)C>C(Cl)Cl>[CH3:22][C:19]1[O:18][C:17]([CH2:16][CH2:15][NH2:14])=[N:21][N:20]=1
Reactant: Cc1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(CCN)o1

Procedure:
TFA (1 ml) is added to a stirred solution of [2-(5-methyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (0.077 g, 0.34 mmol) in DCM (5 ml). After 1 hour at room temperature the solvents are removed. The residue is dissolved in DCM and washed with 4M aqueous NaOH solution. The organic extract is separated, dried (MgSO4) and the solvent removed to give the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15]N1C(=O)CCC1=O.[OH-].[Na+].C(OC(=O)C)C>C(#N)C>[Cl:15][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:7]=1[NH2:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 97.1 %

Procedure:
4-Nitro-2-trifluoromethylaniline (15 g) and N-chlorosuccinimide (10.7 g) dissolved in acetonitril (100 ml) was heated to 150° C. for 15 minutes in a sealed microwave process vial. The reaction mixture was cooled to ambient temperature and poured into 5% sodium hydroxide (500 ml) and ethylacetate (400 ml). After seperation the organic phase was dried (MgSO4), filtered and concentrated in vacuo, followed by purification by flash chromatography to furnish 17.0 g (97% yield) of the title compound as a yellow solid. LC-MS (m/z) 240 (MH+); tR=4.76, (UV, ELSD) 97%, 96%. 1H NMR (500 MHz, DMSO-d6): 7.15 (s, 2H), 8.15 (d, 1H), 8.40 (d, 1H).