Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].[NH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:20]([O:19][C:17]([CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][N:7]1[C:1](=[O:6])[C:2](=[O:3])[CH3:4])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)[C@@H]1Cc2ccccc2CN1
Reactant: CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(=O)N1Cc2ccccc2CC1C(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 16 h

Procedure:
A cooled and freshly distilled solution of 270 mg of pyruvic acid in 5 ml of chloroform is rapidly stirred into a solution of 700 mg of Tic-OBut and 630 mg of dicyclohexylcarbodiimide in 15 ml of anhydrous chloroform, the latter solution having been cooled to -50° C. The mixture is left for 16 hours in a deep-freezing cabinet (-20° C.), and the precipitated dicyclohexylurea is filtered off. The solution is washed with KHSO4 solution and then with KHCO3 solution, dried over Na2SO4, and concentrated in vacuo. The compound (oil) contains a little dicyclohexylurea, and was analyzed by chromatography over silica gel in the system CHCl3 /CH3OH 15:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (35.71 g, 140 mmol) was dissolved in a mixture of ethyl acetate (110 mL) and methanol (110 mL). 50% wet 10% palladium on carbon (3.3 g) was added to the mixture. Reaction vessel was charged with 55 psi of hydrogen gas. Reaction shook on a Parr apparatus at room temperature for 16 hours. Reaction mixture was filtered to remove the catalyst. Filtrate was concentrated in vacuo. Title compound was obtained as clear colorless oil in 97% yield. 1H NMR (300 MHz, CDCl3): δ=4.04 (d, J=10.25, 2H), 3.64 (s, 3H), 2.68 (t, J=12.44, 2H), 2.21 (d, J=6.95, 2H), 1.98-1.77 (m, 1H), 1.64 (d, J=13.54, 2H), 1.41 (s, 9H), 1.25-0.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].O>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[Si:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: C[Si](C)(C)Cl
Reactant: Clc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1sccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to the procedure described in WO9412505. To a solution of 3-chlorothiophene (7.00 g, 59.0 mmol) in 60 mL anhydrous THF under nitrogen was added n-butyllithium, 2.5 M in hexanes (23.6 ml, 59.0 mmol) dropwise from a plastic syringe over 15 min. The reaction became cloudy with a white ppt. The reaction was allowed to stir for 40 min, at which point trimethylsilyl chloride (8.24 ml, 64.9 mmol) was added dropwise via syringe over 5 min. The mixture was allowed to stir for 10 min, and was then warmed to 0° C. for 10 min, and 7 mL water and 35 mL brine were added. The mixture was diluted with EtOAc, and the layers separated. The aqueous layer was extracted once with EtOAc. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (3-chlorothiophen-2-yl)trimethylsilane as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31](=[O:35])[NH:32]2)=[CH:28][CH:27]=1)(=[O:24])[CH3:23].N1CCCCC1.C(OCC)(=O)C>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:8]=[C:30]1[C:29]2[C:33](=[CH:34][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=2)[NH:32][C:31]1=[O:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: CC(C)(C)c1cc(C=O)ccc1OCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc(OCCN2CCOCC2)c(C(C)(C)C)c1
Reaction time: 12 h
Yield: 25.6 %

Procedure:
A mixture of 3-tert-butyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.25 g), 6-acetamido-2-oxindole (0.16 g) and piperidine (0.43 ml) in ethanol (3 ml) was held in a sealed tube at 100° C. for 12 hours. The reaction was cooled, added to ethyl acetate (250 ml), washed with 1N hydrochloric acid (100 ml) and brine (100 ml), dried with magnesium sulfate and concentrated. Some product went into the acid wash, so this was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2×150 ml). The organic layers were dried over magnesium sulfate, combined with the oil from the first crop of product and concentrated. Chromatography (silica, 40% ethyl acetate followed by 5-10% methanol/methylene chloride) afforded 100 mg (27%) of N-{3-[3-tert-butyl-4-(2-morpholin-4-ylethoxy) benzylidene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[CH:17]=[N:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:28]1([CH2:27][N:14]2[C:13](=[O:22])[N:12]3[C:20]4[N:19]([C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=5)=[CH:10][CH2:11]3)[N:18]=[CH:17][C:16]=4[C:15]2=[O:21])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cnn3c2n(c(=O)n1Cc1ccccc1)CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4.0 g of 8-(3-(trifluoromethyl)phenyl)-3H,6H-1,4a,8a-tetraazaacenaphthylene3,5(4H)-dione (prepared as described in Example 14) in 40 ml of dry N,N-dimethylformamide, under nitrogen, is added 650 mg of 60 percent sodium hydride (dispersion in mineral oil). The mixture is stirred at room temperature for 2 hours, then 2.5 g of benzyl bromide is added and the mixture is stirred for 40 hours.
Reaction SMILES: [Na].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCN1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.2 g. of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride) suspended in 270 ml. of dimethylformamide are added in four portions at -10° C. to a solution of 37.0 g. of p-methoxybenzoyl chloride in 50 ml. of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and then at 40° C. for 4 hours. The solvent is evaporated and the residue is treated with diethyl ether and with cold sodium bicarbonate solution. The insoluble crystalline constituents are filtered off, washed with water and diethyl ether and dried in vacuo over phosphorus pentoxide. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 120°-121° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43](Cl)=[O:44].C(N(C(C)C)CC)(C)C>ClCCl>[S:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:44]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)c1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3nc4ccccc4s3)CC2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 63 mg, 0.13 mmol), benzothiazole-2-carbonyl chloride (available from Alfa Aesar, Ward Hill, Mass., USA; 33 mg, 0.17 mmol), and diisopropylethylamine (0.14 mL, 0.8 mmol) in dry dichloromethane (4 mL) was stirred at room temperature over the weekend. The solution was diluted with dichloromethane (6 mL) and washed with 1 M aqueous hydrochloric acid (5 mL), water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was evaporated and the crude product was purified by HPLC to give benzothiazol-2-yl-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (43 mg, 62%) as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(C)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An aqueous solution of sodium hydroxide (9.2 g) was added to an ice-cooled, stirred solution of methyl 2-chloro-5-methylnicotinoate (35.28 g) in methanol at such a rate so that the temperature of the reaction mixture did not exceed 30° C. The mixture was then stirred at room temperature for 1.5 hours. Solvent was evaporated. The residue was diluted with water and acidified to pH 2 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to yield the title compound as a pale yellow solid, 31.92 g, m.p. 180°-180.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([C@@H](Cl)C([O-])=O)[C:10]2=[O:19])=[O:8])=[CH:5][CH:4]=1.NC(N)=S.C([OH:28])C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:10](=[O:19])[CH:11]([OH:28])[CH2:12][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)N2CC[C@H]([C@@H](Cl)C(=O)[O-])C2=O)cc1
Reactant: CCO
Agent: NC(N)=S
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCC(O)C2=O)cc1
Reaction time: 8 h

Procedure:
1.54 g of (R,S)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinylchloroacetate are heated at 100° C. in 50 ml of pyridine for 10 minutes under nitrogen with 0.42 g of thiourea and 7 ml of ethanol. The solvent is removed by evaporation and the residue is partitioned between ethyl acetate and water. The organic phase is washed several times with water and the aqueous phases are extracted with ethyl acetate. The combined ethyl acetate phases are evaporated, the residue is boiled at reflux in diisopropyl ether and then the solution is decanted off from insoluble constituents. The clear, colourless diisopropyl ether phase is stirred in an ice-bath and then left to stand in an ice box overnight. The product which crystallises out is filtered off and there is obtained (R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 125°-126° C.
Reaction SMILES: [C:1](=[N:11][OH:12])([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13](OC(OCC)OCC)C>B(F)(F)F.CCOCC>[CH:2](/[C:1]1[N:10]=[CH:13][O:12][N:11]=1)=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(C=Cc1ccccc1)=NO
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: C(=C/c1ncon1)\c1ccccc1
Reaction time: 1 h

Procedure:
Cinnamamidoxime (6.5 g.) (H. Wolff, Ber., 1886, 19, 1507) was refluxed in triethylorthoformate (60 ml.) containing two drops of boron trifluoride etherate. Thin layer chromatography showed that receiving was complete after 1 hr. and the reaction mixture was evaporated in dryness in vacuo. The residue was dissolved in chloroform (100 ml.) and washed consecutively with 2N-hydrochloric acid (100 ml.), saturated sodium bicarbonate solution (100 ml.) and water (100 ml.). The chloroform solution was evaporated to dryness in vacuo and the resultant yellow crystals were recrystallised from aqueous methanol to yield needle-like crystals of 3-(β-trans-styryl)-1,2,4-oxadiazole 5.82 g. (84%), m.p. 82°, λmax (EtOH) 275 nm., ε23200, τ(CDCl3) 1.33 (1H), 2.56 (aromatic multiplet), 2.24 (doublet, J=16 c./sec.), 2.88 (doublet, J=16 c./sec.) (Found: C, 69.9; H, 4.7; N, 15.9. C10H8N2O requires C, 69.75; H, 4.7; N, 16.3%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH2:24]([N:28]=[C:29]=[O:30])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:29]1=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: CCCCn1c(=O)c2cnc3c(OC)cccc3c2n(C2CCCC2)c1=O
Yield: 70.8 %

Procedure:
3-Butyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and butyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 368 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.47 (s, 1H), 7.81 (d, 1H), 7.57 (t, 1H), 7.23 (d, 1H), 4.99 (p, 1H), 4.14 (s, 3H), 4.06 (t, 2H), 2.42 (m, 2H), 2.08 (m, 4H), 1.69 (m, 4H), 1.44 (q, 2H), 0.97 (t, 3H) ppm.
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])=[S:20])=[C:14]([OH:32])[C:13]=1[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34].[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].N1C=CN=C1>>[F:31][C:28]([F:29])([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:14]=1[O:32][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2C(F)(F)F)c1O
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2C(F)(F)F)c1O[Si](C)(C)C(C)(C)C
Yield: 44 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-trifluoromethylphenyl)thiourea (416 mg, 1.0 mmol), tert-butyldimethylsilyl chloride (750 mg, 5.0 mmol) and imidazole (136 mg, 2.0 mmol) were reacted to form the desired product (250 mg, 45%). EI-MS m/z 568.0 (M+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]1([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:45]2[CH2:46][CH2:47][N:42]([C:34]3[N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)[CH2:43][CH2:44]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-n2c(N3CCNCC3)nc3ccccc32)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4n3-c3ccccc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-phenyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=410.6 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:40]([NH2:45])[CH2:41][CH2:42][CH2:43][CH3:44]>O1CCCC1>[CH2:40]([NH:45][C:18](=[O:20])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCCN
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
2 g (0.06 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 20 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 0.76 ml (0.06 mol) of N-ethylmorpholine and 0.79 ml (0.006 mol) of isobutyl chloroformate were added and the resulting mixture was stirred at -10° C. for 20 minutes. 0.69 ml (0.006 mol) of n-pentylamine was then added and the resulting solution was stirred at -20° C. for 1 hour and then left to stand at room temperature overnight. The solution was then evaporated to an oil which was dissolved in ethyl acetate. The ethyl acetate solution was washed twice with water, twice with 5% citric acid solution, once with water, twice with 5% sodium bicarbonate solution and twice with water, dried and evaporated to an oil. The desired N-benzyloxycarbonyl-L-alanyl-L-proline n-pentylamide was crystallised from ethyl acetate/petroleum ether in a yield of 1 g (42.8%) and with a melting point of 102°-104° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)O1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane and 2M Na2CO3 was added 4-chloro-3-nitropyridine (1.2 equiv.) and Pd(PPh3)4 (0.05 equiv.). The reaction was heated in an oil bath to 120° C. for 30 min. (reaction can also be carried out in the microwave for 10 min at 120° C.). Cooled to room temperature, then diluted with EtOAc, added H2O—dark solution, lots of emulsions. Filtered to get rid of the solids, then extracted the organic phase, dried with Na2SO4, and concentrated. The crude was purified via silica gel chromatography to yield 3-(3-nitropyridin-4-yl)cyclohex-2-enone (64%, 2 steps). LC/MS=219 (M+H), LC=2.29 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:28][CH:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:30]>>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:28][CH:29]([CH3:30])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:15]([S:18]([CH:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Product: CC(NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C)C(C)(C)C
Yield: 80 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 0.6 mmol) was stirred in 2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and evaporated to afford 450 mg (80%) of the title compound as pale yellow crystals. Mp 177-180° C. 1H NMR (200 MHz, CDCl3): δ=0.89 (s, 9H), 1.04 (d, 3H), 1.40 (d, 6H), 2.97 (m, 1H), 3.27 (m, 1H), 7.50 (s, 2H), 7.67 (s, 1H), 9.16 (brs, 1H);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][OH:16]>>[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cccc(CO)c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: Cc1cccc(COc2ccncc2[N+](=O)[O-])c1
Yield: 89.8 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 3-methylbenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 89.8%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11]>C(O)C.[Pd]>[NH2:8][C:4]1[C:3]([OH:11])=[C:2]([F:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1nccc(F)c1O
Agent: [Pd]
Solvent: CCO
Product: Nc1nccc(F)c1O
Reaction time: 1.5 h

Procedure:
Under argon, 90 mg (0.57 mmol) of 4-fluoro-2-nitropyridin-3-ol Example 108A were dissolved in 30 ml of ethanol, and a spatula tip of palladium on activated carbon (10%) was added. The mixture was hydrogenated at RT under reduced pressure for 1.5 h. The reaction mixture was filtered off through silica gel and the filter cake was washed with plenty of ethanol. The solution was concentrated and dried. This gave 56 mg (77% of theory) of the title compound.