Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:17]=[C:16]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43].ClCCl>O>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:17]=[C:16]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:42]([CH3:43])=[O:44]
Reactant: Nc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
5-(3′-Amino-biphenyl-4-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (8.0 mg, 0.02 mmol) prepared in Example 253, pyridine (2.2 uL, 0.02 mmol) and acetyl chloride (1.4 uL, 0.02 mmol) were added at 0° C. to dichloromethane (0.3 mL). The reaction mixture was stirred at room temperature for 2 hours and then distilled water was added thereto. The reaction mixture was extracted with dichloromethane two times. The combined extract was washed with a 1N hydrochloric acid solution, a saturated solution of sodium carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 1.9 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][OH:20])([CH3:18])[CH2:13]3)[O:7][C:6]=2[CH:21]=1.[H-].[Na+].I[CH3:25].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][O:20][CH3:25])([CH3:18])[CH2:13]3)[O:7][C:6]=2[CH:21]=1
Reactant: CI
Reactant: C[C@]1(CO)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@]1(C)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
[(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol (2.5 g, 8.5 mmol) in tetrahydrofuran (10 ml) was added slowly to a mixture of sodium hydride, 60% in oil (1.354 g, 33.9 mmol) and tetrahydrofuran (15 ml). The reaction mixture was heated at 60° C. for 2 hours after the mixture was cooled down and iodomethane (0.685 ml, 11.0 mmol) in tetrahydrofuran (3 ml) was added. The mixture was stirred at RT for 1 hour, water (25 ml) was added carefully and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness. Ethyl acetate (20 ml) was added to the evaporation residue and was made acidic with aq HCl. The layers were separated and the water layer was made basic with aq NaOH and extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness to yield 2.34 g (89%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[N:18]=[N:19][NH:20][N:17]=4)[CH:14]=3)[NH:9][N:8]=2)[CH:2]=1
Reactant: N#Cc1ccc2[nH]nc(-c3cccnc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1cncc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1

Procedure:
The title compound was prepared from 3-(3-pyridyl)-1H-indazole-5-carbonitrile (0.068 g, 0.031 mmol), azidotributyl tin (0.116 g, 0.096 mL, 0.32 mmol) in toluene (10 mL). The product was isolated using the procedure described for Example 161 (0.009 g, 0.04 mmol, 12.5% yield): 1H NMR (DMSO-d6) δ 14.0 (br s, 1H), 9.2 (d, 1H), 8.8 (s, 1H), 8.7 (d, 1H), 8.5 (d, 1H), 7.83–7.78 (m, 2H), 7.76–7.64 (m, 1H); ES-MS (m/z) 264 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C(CCn1ccnc1)c1ccc(F)cc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCn1ccnc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-(1-(1H)-imidazolyl)-1-propanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.46 g), 3 equivalents of pyridine and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was partitioned between 20% sodium hydroxide solution and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.9 g (40%) of product, mp 225°-226° C. (dec).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(Cl)[N+]=1[O-:15]>[2H]C1C([2H])=C([2H])C([2H])=C([2H])C=1[2H]>[C:1]1(=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: C1CCCCC1
Agent: [2H]c1c([2H])c([2H])c([2H])c([2H])c1[2H]
Product: O=C1CCCCC1
Product: OC1CCCCC1
Temperature: 75 °C

Procedure:
A solution containing 1M cyclohexane, 0.625M 2,6-dichloropyridine N-oxide and 0.10 mM [Ru(TPFPP)(NO)(H2O)](SbF6) in 1 ml d6 -benzene was heated for eight hours in a sealed tube at 75° C. affording high yields of oxidized products. A combined yield of 93% and 1500 catalytic turnovers were obtained of two products, cyclohexanone and cyclohexanol (mole ratio 4:1). In CD2Cl2 the same reaction conditions proceeded to give 5600 turnovers to generate cyclohexanone and cyclohexanol (8:1) in a combined 98% yield in twelve hours. 2,6-dichloropyridine-N-oxide was unable to hydroxylate cyclohexane by heat alone as shown by a control experiment, proving that the ruthenium complex must be present to effect reaction. ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[CH2:7]Br.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CN(C)C=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24][CH2:7][C:6]=2[CH:9]=1
Reactant: Clc1ccc(I)c(CBr)c1
Reactant: Oc1ccccc1S
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)CSc1ccccc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A solution of 125.6 g of 5-chloro-2-iodobenzyl bromide in 500 ml of dimethylformamide is added to a mixture of 640 ml of dimethylformamide, 52.4 g of potassium carbonate and 47.8 g of 2-hydroxythiophenol (R. Leuckart, J.Prakt.Chem. /2/ 41, 192, 1890). Then, the mixture is stirred for 1 hour at room temperature, treated with 57 g. of potassium carbonate and 4.5 g of copper and is refluxed for 6 hours. Dimethylformamide is distilled off under reduced pressure, the residue diluted with water and shaken with benzene. After filtration, the benzene layer is separated, washed with water, dried with potassium carbonate and evaporated. By distillation of the residue there are obtained 42.5 g (45%) of 2-chloro-11H-dibenz(b.f)-1,4-oxathiepin with a b.p. of 148°-168° C./85 Pa and m.p. of 66.76° C. The pure product is obtained by crystallization from methanol and melts at 78°-79° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:12])[CH2:9][CH2:10]Br)[CH2:3]1.Cl.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>C(N(CC)CC)C>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:12])[CH2:9][CH2:10][N:21]2[C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][C:17]=3[C:26]3[CH2:25][N:24]([CH3:23])[CH2:29][CH2:28][C:27]2=3)[CH2:3]1
Reactant: NC1CCCN(C(=O)CCBr)C1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCCC(N)C2)CCN(C)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(3-aminopiperidin-1-yl)-3-bromopropan-1-one, 4-methylphenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:19][N:20]=[C:21]([C:23]1[O:27][C:26]([N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:25][CH:24]=1)[CH3:22]>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:19][N:20]=[C:21]([C:23]2[O:27][C:26]([N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:25][CH:24]=2)[CH3:22])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NO)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NOCc2ccc(C(F)(F)F)cc2)o1
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (200 mg, 0.84 mmoles) in DMF (2 mL), cesium carbonate (408 mg, 1.26 mmoles) was added followed by addition of diethyl 2,2′-((5-(1-(hydroxyimino)ethyl)oxazol-2-yl)azanediyl)diacetate (262 mg, 0.84 mmoles) at 25° C. under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography (Eluent: 15% ethyl acetate in hexane) to yield 295 mg (75%) product as thick liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylate (810 mg, 2.07 mmol) and lithium hydroxide hydrate (434 mg, 10.3 mmol) in methanol (30 ml) and water (5 ml) was stirred for 18 hours at 25° C. The mixture was adjusted to pH=7 using hydrochloric acid (2 molar, 5.15 ml) and then evaporated to dryness under reduced pressure. 1-Methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (1.38 g) as light brown solid was used without further purification. MS: m/z=364.1 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]I.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[N:1]1([C@@H:2]([CH3:5])[CH2:3][OH:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ICCCCCI
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H](CO)N1CCCCC1
Yield: 54 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (2.0 mL, 26 mmol), 1,5-diiodopentane (4.7 mL), and sodium carbonate (7.13 g, 67.3 mmol) in i-propanol (200 mL) was heated at reflux overnight. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL) and the insoluble solid was filtered off. The solvent was removed under reduced pressure and the residue was purified on a silica gel column to yield ((S)-2-(piperidin-1-yl)propan-1-ol (2.0 g, 54%) as a clear oil. 1H NMR (CDCl3): δ 3.37 (dd, 1H), 3.30 (t, 1H), 2.78 (m, 1H), 2.62 (m, 2H), 2.33 (m, 2H), 1.40-1.70 (m, 6H), 0.86 (d, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:10]([NH:8][CH:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)=[O:11])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: CC1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)CC1

Procedure:
As described for example 78, 4-methylcyclohexylamine (206.1 mg, 1.82 mmol), 4-nitrophenyl chloroformate (366 mg, 1.82 mmol), diisopropyl(ethyl)amine (554 mg, 4.3 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (300 mg, 1.21 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:8]1([C:13](=[O:16])NO)[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C1(C)C=CC=CC=1.[OH2:42].[OH-].[Na+]>ClCCl>[C:4]([OH:34])(=[O:3])[CH2:5][CH3:6].[CH2:1]([O:3][C:4]([CH2:5][CH2:6][N:7]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:8]1([C:13]([OH:42])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:34])[CH3:2]
Reactant: O
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC(=O)O
Product: CCOC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.48 g (15.1 mmol) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution was treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture was stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase was separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture was stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase was separated and washed with water. The ethyl acetate solution was slowly treated with 150 mL of hexanes at ambient temperature causing solids to precipitate, and stirred overnight. Filtration yielded 5.01 g of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-1-hydroxycarbamoylcyclopentyl)amino]propionic acid as a white solid (71% yield from 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][C:9]23[CH2:23][CH:16]([C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=42)[C:17]2[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1
Reactant: CN1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1
Reaction time: 6 h

Procedure:
A mixture of 9-(4-methyl-3-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (170 ml) and lithium aluminum hydride (100 mg) in dioxane was stirred at 60° - 70° C. for 6 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-methyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 136° - 137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:31]I.O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:31])[C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.25 mmol) of N-(2-fluoro-4-nitrophenyl)-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine in 0.75 ml of DMA is added dropwise to a suspension of 30 mg (0.75 mmol) of sodium hydride in 0.75 ml of DMA, and the mixture is stirred at RT for 30 min. 77 μl (1.24 mmol) of methyl iodide are then slowly added dropwise, and the mixture is stirred for a further 30 min. Water is then added, and the mixture is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue is purified by preparative HPLC.
Reaction SMILES: [OH2:1].C(#N)C.[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>ClCCl.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH:14]1([CH2:13][CH2:12][CH2:11][C:5]([OH:27])=[O:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc(CCCC2CCCCCCCCCCC2)cc1
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)CCCC1CCCCCCCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 90 mL of water, 60 mL of acetonitrile and 60 mL of carbon tetrachloride is added 4.8 g (16.8 mmol) of 1-(3-phenylpropyl)cyclododecane, 50.0 g (0.25 mol) of sodium periodate and then 70 mg (0.3 mmol) of ruthenium trichloride hydrate. The reaction mixture is allowed to stir at room temperature overnight. The mixture is then taken up in dichloromethane and 1N HCl and the layers separated. The aqueous phase is washed 3 times with dichloromethane and the combined organic layers are dried over MgSO4 and the solvents evaporated. The residue is taken up in ether, filtered through Celite and the filtrate evaporated. The crude product is flash chromatographed using acidic silica gel and 30% ethyl acetate/hexanes to give 3.25 g of a white solid: NMR (CDCl3) δ1.2-1.5 (m, 10H), 1.65 (m, 2H), 2.35 (t, 2H, J=8 Hz).
Reaction SMILES: C([C:3]1([C:19]([O-:21])=[O:20])[O:7][C:6]2=[C:8]([O:16]C)[CH:9]=[CH:10][C:11](C)([C:12]([O-:14])=[O:13])[C:5]2=[C:4]1[CH3:18])C.CN(C)P(=O)(N(C)C)N(C)C.O.[C:34]1(C)C=CC=C[CH:35]=1>>[CH2:34]([O:21][C:19]([C:3]1[O:7][C:6]2[C:8]([OH:16])=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:5]=2[C:4]=1[CH3:18])=[O:20])[CH3:35]
Reactant: CCC1(C(=O)[O-])OC2=C(OC)C=CC(C)(C(=O)[O-])C2=C1C
Reactant: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1oc2c(O)ccc(C(=O)O)c2c1C
Temperature: 25 °C

Procedure:
The solution of 2-ethyl-4-methyl-7-methoxy-3-methylbenzo[b]furan-2,4-dicarboxylate (from step 5 of example 1) (13.0 g), sodium p-thiocresolate (20.26 g, 1.5 equiv.) and hexamethylphosphoric acid triamide (24.80 g, 1.5 equiv.) was heated in dry toluene at reflux temperature under nitrogen for 2-6 h. The reaction mixture was cooled to room temperature, water was added and aqueous layer was washed with dichloromethane. Aqueous layer was acidified at 10-15° C. with concentrated hydrochloric acid. The precipitated product was filtered and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:10](=[O:27])[N:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:12]=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.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>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[C:10](=[O:27])[C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[C:14]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:13]=[N:12]2)=[CH:21][CH:22]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: O=c1c(Oc2ccc(Br)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1c(Oc2ccc(-c3ccncc3)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1

Procedure:
1.5 mmol of 4-(4-bromophenyl)oxy-2-(4-chlorophenyl)-5-(1H-imidazol-1-yl)-3(2H)-pyridazinone, 2.1 mmol of 4-trimethylstannylpyridine, 0.1 mmol of bis(triphenyl-phosphine)palladium dichloride and 1.3 mmol of ethyldiisopropylamine in 5 ml of dimethylformamide are heated at 100° C. for 5 hours. The solvent is removed in a rotary evaporator, and the residue is purified by chromatography on silica gel (elution with ethyl, acetate/methanol mixtures). 0.3 g (45% of theory) is obtained of m.p. 188° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:6]([CH:8]1[CH2:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]1=O)=O.O.[NH2:27][NH2:28].C(O)(=O)C>C(O)C>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[CH2:15][C:11]4[S:12][CH:13]=[CH:14][C:10]=4[C:9]=3[NH:28][N:27]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: NN
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1Cc2sccc2C1=O
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)c1cc(-c2n[nH]c3c2Cc2sccc2-3)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
5-(3,5-Bis-trifluoromethyl-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.07 g, 4.1 mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol), glacial acetic acid (0.8 mL) and ethanol (10 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(3,5-Bis-trifluoromethyl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.58 g, 1.5 mmol) as white solid in 37% yield.