Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH2:18])=O.S(Cl)(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]#[N:18]
Reactant: NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxamide (2.36 grams, 0.073 mole) was suspended in 30 ml of toluene, 10 ml of thionyl chloride, and about 1 ml of DMF. The suspension was stirred and heated to reflux, then refluxed for 11/2 hours. Solvent and excess thionyl chloride was removed in vacuo. The crude solid was crystallized from toluene yielding 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonitrile, yield 0.7 gram, mp=83°-85° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:32][C:33](=O)[CH2:34][C:35]1[NH:39][CH:38]=[N:37][N:36]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[C:33](=[O:32])[CH2:34][C:35]1[NH:36][N:37]=[CH:38][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Product: COc1ccc(N2CCN(C(=O)Cc3ncn[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 0.7 %

Procedure:
Prepared using the same procedure described in Example 275 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 7 days to afford the title compound as a colorless solid (0.9 mg, 0.7%). LC/MS (Method B) 3.32 min, [M+1]+ 511.
Reaction SMILES: ClC1C=CC2CCNC[C@@H](C)C=2C=1Cl.[CH3:15][N:16]1[CH2:22][C@H:21]([CH3:23])[C:20]2[C:24]([Cl:29])=[C:25]([Cl:28])[CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:22][C@@H:21]([CH3:23])[C:20]2[C:24]([Cl:29])=[C:25]([Cl:28])[CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17]1
Reactant: C[C@H]1CN(C)CCc2ccc(Cl)c(Cl)c21
Agent: C[C@@H]1CNCCc2ccc(Cl)c(Cl)c21
Product: C[C@@H]1CN(C)CCc2ccc(Cl)c(Cl)c21

Procedure:
Compound 10 was prepared from (S)-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8 Hz, 1H), 6.89 (d, I=8 Hz, 1H), 3.91-3.88 (m, 1H), 3.28 (ddd, J=15, 12, 2 Hz, 1H), 2.99-2.88 (m, 2H), 2.68 (ddd, J=15, 5, 1 Hz, 1H), 2.36-2.32 (m, 4H), 2.13 (t, J=11 Hz, 1H), 1.27 (d, J=7 Hz, 3H). MS calculated for C12H15Cl2N+H: 243, observed: 243.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([Sn](CCCC)(CCCC)CC=C)[CH2:11][CH2:12]C.[Li+].[Cl-]>C1(C)C=CC=CC=1.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>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH:11]=[CH2:10]
Reactant: N#Cc1cccc(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cccc(C#N)c1

Procedure:
To solution of compound 3-bromobenzonitrile (5 g, 27 mmol) and tributyl(prop-2-en-1-yl)stannane (13.5 g, 41.2 mmol) in toluene was added Pd(PPh3)4 (300 mg) and LiCl (2.3 g, 54 mmol) under N2, and then the mixture was stirred at reflux for 18 h. The reaction mixture was quenched by the addition of water. Extracted the mixture with EtOAc and the organic layer was dried and concentrated. The residue was purified by a flash column chromatography to afford 3-(prop-2-en-1-yl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ 7.32˜7.82 (m, 4H), 5.85˜6.00 (m, 1H), 5.05˜5.17 (m, 2H), 3.42 (d, J=6.8 Hz, 2H).
Reaction SMILES: C(OC([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]1)=O)(=O)C1C=CC=CC=1.[BrH:49].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:49].[BrH:49].[CH2:26]([O:25][C:23]([C@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH:15]1[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OC(=O)c2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 1 ml of acetic acid is dissolved 0.45 g of tert-butyl 3(R)-[5-(1-benzoyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 1 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.3 g of 3(R)-[1(R)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-acetic acid.dihydrobromide as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[OH:21])=[O:13])[CH:8]=[C:7]2[CH:22]=O.Cl.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2([F:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1.C(O)(=O)C.C([BH3-])#N>ClCCCl.C(N(CC)CC)C.C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2([F:39])[CH2:34][CH2:35][N:36]([CH2:22][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[C:9]([C:12]([NH:14][C@H:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]4[OH:21])=[O:13])[CH:8]=3)[CH2:37][CH2:38]2)[CH:28]=1
Reactant: O=Cc1cc(C(=O)N[C@H]2CCCC[C@@H]2O)nc2c(F)cccc12
Reactant: FC1(c2cc(Cl)ccn2)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(CN2CCC(F)(c3cc(Cl)ccn3)CC2)c2cccc(F)c2n1
Reaction time: 0.08 h

Procedure:
To a solution of 8-fluoro-4-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (C9) (0.080 g, 0.25 mmol) in DCE (3 mL) was 4-chloro-2-(4-fluoropiperidin-4-yl)pyridine dihydrochloride (C5) (0.080 g, 0.28 mmol) and triethylamine (6 drops). After 5 min, acetic acid (0.043 mL, 0.76 mmol) and MP-cyanoborohydride were added. The mixture was irradiated in a microwave reactor at 100° C. for 20 min, then diluted with CH2Cl2 and was washed with brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-5% methanol in dichloromethane to provide the title compound (Example C) as a white solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 515.0 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 7.60-7.55 (m, 2H), 7.47-7.42 (m, 1H), 7.22-7.20 (m, 1H), 4.03 (s, 2H), 3.94-3.86 (m, 1H), 3.63-3.56 (m, 1H), 3.42 (br s, 1H), 2.86-2.83 (m, 2H), 2.62-2.56 (m, 2H), 2.47-2.30 (m, 2H), 2.17-2.11 (m, 2H), 1.89-1.78 (m, 4H), 1.56-1.31 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nccnc1N1CCNCC1
Solvent: ClC(Cl)Cl
Product: Clc1cnc(N2CCNCC2)c(Cl)n1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a suspension of 2-chloro-3-(1-piperazinyl)pyrazine (11.7 g, 58.7 mmol; from Example 90, Step 1) in CHCl3 (50 mL) was N-chlorosuccinimid (14.4 g, 108 mmol) added and the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and extracted twice with water. The combined aqueous phases were made alkaline (11 M NaOH), saturated with NaCl, cooled, and extracted with EtOAc (×3). Concentration of the combined, dried (MgSO4), organic phases afforded 6.12 g (45%) of the title compound as a brown oil which crystallized upon standing: mp 89-97° C. Anal. (C8H10Cl2N4.⅓H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])([O-])=O>C(O)C.[Pd].Cl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)C(=O)c1ccccc1N
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a solution of 1-(2-nitrophenyl)-2,2-dimethylpropan-1-one (5 g, 24 mmol) (ref: Aus. J. Chem., 34, 1875-8 (1981)) in ethanol (100 ml) was added 10% palladium on carbon (0.5 g, 10% (w/w)) in hydrochloric acid (5 ml of a 5M solution). The mixture was hydrogenated at 25 psi for 20 min, then the catalyst was filtered off and washed with methanol. The solvents were evaporated in vacuo. The oily residue was partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml). The organic phase was separated, washed with brine (25 ml), dried (Na2SO4) and evaporated. Trituration of the solid with diethyl ether afforded the title compound as a colourless solid (3 g, 70%). 1H NMR (250 MHz, CDCl3) δ 1.38 (9H, s), 5.64 (2H, brs), 6.60-7.30 (4H, m).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19](O)[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cc3)nc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)cc3)nc2c1
Yield: 80.1 %

Procedure:
A solution of 2-(4-isopropoxyphenyl)-7-methoxyquinazolin-4-ol (495 mg, 1.595 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 4-chloro-2-(4-isopropoxyphenyl)-7-methoxyquinazoline (420 mg, 80% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.59-8.53 (m, 2H), 8.11 (d, J=9.3 Hz, 1H), 7.24 (dd, J=9.2, 2.4 Hz, 1H), 7.04-7.00 (m, 3H), 4.70 (quin, J=6.0 Hz, 1H), 4.03 (s, 3H), 1.40 (d, J=6.0 Hz, 6H); MS: MS m/z 329.1 (M++1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH:18]=1)[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].ClC1C=CC(S(O[CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])(=O)=O)=CC=1.O>CS(C)=O>[C:21]1([CH2:20][O:19][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:38][C@@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[CH:18][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (36.0 mg, 1.50 mmol) was added to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 400 mg, 1.25 mmol) in dimethylsulfoxide (8 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. 1,1-Dimethylethyl (2S)-2-({[(4-chlorophenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (444 mg, 1.25 mmol) in dimethylsulfoxide (7 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product, which was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to yield the title compound as a yellow oil. 0.60 g.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:13]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(I)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: Ic1ccc(CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
Into a 50-mL 3-necked round-bottom flask under N2 was placed a solution of 2-(4-iodophenyl)ethanol (470 mg, 1.90 mmol) in tetrahydrofuran (10 mL). Sodium hydride (91 mg, 3.8 mmol, 1.2 equiv.) was added at 0° C. The mixture was warmed to room temperature and stirred at room temperature for 2 h. Benzyl bromide (272 μL, 3.9 mmol, 1.2 equiv.) and tetra-n-butylammonium bromide (61 mg, 0.19 mmol, 0.10 equiv.) were added at room temperature. The resulting solution was stirred for 20 h at room temperature. The reaction was then quenched by the addition of 10 mL of aqueous NH4CI. The solution was extracted with 3×60 mL of EtOAc, and the organic layers were combined and washed with 50 mL of brine. After evaporation, the residue was applied onto a silica gel column, and the product was eluted with EtOAc/petroleum ether 1:20 to furnish 600 mg (94%) of 1-[2-(benzyloxy)ethyl]-4-iodobenzene as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:29])[CH:5]=[CH:6][C:7]1([OH:28])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[N:17][N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][O:24][CH3:25])[CH2:9][C:8]1([CH3:27])[CH3:26]>CC(C)=O.O=[Mn]=O>[OH:28][C:7]1([CH:6]=[CH:5][C:4]([CH3:29])=[CH:3][CH:2]=[O:1])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[N:17][N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][O:24][CH3:25])[CH2:9][C:8]1([CH3:26])[CH3:27]
Reactant: COCC1CCCN1N=C1CC(C)(C)C(O)(C=CC(C)=CCO)c2ccccc21
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: COCC1CCCN1N=C1CC(C)(C)C(O)(C=CC(C)=CC=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A mixture of hydrazone alcohol [29] (69 mg, 0.17 mmol) and MnO2 (300.8 mg, 3.46 mmol) in acetone (5 mL) was stirred at RT for 16 hr. The reaction mixture was filtered over a bed of Celite® and washed with acetone. The combined filtrates and washings were evaporated to give a residue, which was purified by column chromatography on silica using 30% ethyl acetate-hexane to provide the hydrazone aldehyde [30] (54.4 mg, 79%) and [α]D−532.6 (c 0.43, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:10][C:4]=2[O:3]1.[H][H]>>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:18]([Cl:32])=[CH:19][C:20]([OH:24])=[CH:21][C:22]=3[Cl:23])=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)cc2O1
Reactant: [H][H]
Product: CC1(C)Oc2ccc(OCCCCOc3c(Cl)cc(O)cc3Cl)cc2O1

Procedure:
As depicted in scheme 1, for example the known compound 2,6-dichloro-4-phenylmethoxyphenol (A) was reacted with a haloalkane of suitable chain length, such as 1-bromo-4-chlorobutane, under basic conditions, affording the corresponding 4-chlorobutoxy derivative (A1). Intermediate (A1) was in turn was reacted under basic conditions with the known hydroxy compound 2,2-dimethylbenzo[d]1,3-dioxolan-4-ol yielding the corresponding coupled compound 2-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-5-oxy)butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (A2). Intermediate (A2) wha then treated with hydrogen gas under catalytic hydrogenation conditions, providing the deprotected intermediate 4-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-5-yloxy)butoxy]-3,5-dichlorophenol (A3). Intermediate (A3) was then reacted with 1,1,1,3-tetrachloropropane, affording a compound of formula I, such as 5-(3,3-Dichloroprop-2-enyloxy)-2-[4-(2,2-dimethylbenzo[d]1,3-dioxolan-4-yloxy)butoxy]-1,3-dichlorobenzene. Example 1 set forth below describes in detail the method by which compounds of formula I were prepared as shown in scheme 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]CCl)=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:25]2[CH:24]=[CH:23][N:22]=[C:21]2[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[N:16]=2)=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCCc1cc(Cl)nnc1CCCl
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMF (30 ml) is added to a mixture of 6-chloro-3-chloroethyl-4-propyl-pyridazine (5.01 g, 24.43 mmol), 2-fluoro-6-(imidazol-2-yl)-pyridine (3.99 g, 24.43 mmol) and anhydrous K2CO3 (10.2 g, 73.3 mmol) and the mixture is stirred at room temperature overnight. The solvent is removed in vacuo, water (30 ml) and EtOAc (30 ml) are added to the residue and the layers are separated. The aqueous layer is extracted with EtOAc (3×30 ml) and the combined extracts are washed with brine (30 ml), dried (Na2SO4) and evaporated, which provides a light brown solid. The solid is washed twice with 1:1 hexane, ether (25 ml), which provides the title compound as a light yellow solid. 1H NMR (CDCl3) 8.12–8.15 (m, 1H), 7.84 (q, 1H), 7.32 (s, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.81–6.84 (m, 1H), 6.22 (s, 2H), 2.68 (t, 2H), 1.54–1.62 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)[OH:13]
Reactant: O=Cc1ccc(F)cc1F
Reactant: Fc1ccc(Br)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: OC(c1ccc(F)cc1)c1ccc(F)cc1F

Procedure:
The title compound was prepared starting from 1.00 g (5.71 mmol) of 4-bromofluorobenzene and 0.97 g (6.86 mmol) of 2,4-difluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 0.53 g (38% of theory) of the title compound was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[N:34][CH:35]=1>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:4](=[O:3])[N:29]([C:30]4[CH:35]=[N:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[CH2:22][CH2:21]3)[CH2:7][CH2:8]2)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C1N(c2ccc(Cl)nc2)CCC12CCN(S(=O)(=O)c1ccccc1)CC2
Yield: 5.3 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (0.9 molar, 1.88 ml) and 5-amino-2-chloro-pyridine (0.145 g) to give the desired 8-benzenesulfonyl-2-(6-chloro-pyridin-3-yl)-2,8-diaza-spiro[4.5]decan-1-one (0.012 g) as a white solid. MS (ESI): 406.1 (MH+).
Reaction SMILES: N#N.Br[C:4]1[N:5]=[C:6]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[Li]CCCC.CN(C)[C:25](=[O:27])[CH3:26].[NH4+].[Cl-]>CCOCC>[C:12]([SiH2:11][O:10][C:9]([CH3:17])([CH3:16])[C:6]1[S:7][CH:8]=[C:4]([C:25](=[O:27])[CH3:26])[N:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Br)cs1
Reactant: CC(=O)N(C)C
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1csc(C(C)(C)O[SiH2]C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 4-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-thiazole (1.94 g, 6.29 mmol) in dry Et2O (50 mL) was added n-BuLi (2.76 mL of a 2.5M solution in hexanes, 6.92 mmol) at −78° C. The reaction mixture was then stirred for 30 min at −78° C. before N,N-dimethylacetamide (1.17 mL, 12.58 mmol) was added dropwise. The reaction mixture was allowed to warm up to rt over a period of 1 h and stirred at this temperature for 20 min. Sat. aq. NH4Cl (20 mL) was added, the layers separated and the aq. layer extracted with Et2O (3×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1->5:1 hept-EA) gave the title compound as a yellow solid. TLC:rf (1:1 hept-EA)=0.51. LC-MS-conditions 02: tR=1.11 min; [M+H]+=272.39.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](=O)([O:21]C(C)(C)C)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.CN(C)C1C=CN=CC=1>[NH2:14][C:12]1[N:13]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][N:4]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:3][CH2:2]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1cccc(CN2CCNCC2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-(piperazin-1-ylmethyl)pyridin-2-amine 85 in THF was added di-tert-butyl carbonate (1 eq) and 4-(dimethyl)aminopyridine (catalytic). The reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. Pentane was added and the resulting solid was collected by filtration and dried to afford 86. The Boc protecting group could be removed after coupling with the appropriate carboxylic acid by treatment with TFA/CH2Cl2 for 12 h.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([N:13]([CH3:15])[NH2:14])[CH:4]=1.[CH3:18][CH:19]([CH3:23])[C:20](=O)[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[N:6]=[C:5]([N:13]([CH3:15])[N:14]=[C:20]([CH:19]([CH3:23])[CH3:18])[CH3:21])[CH:4]=1
Reactant: CN(N)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Reactant: CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=NN(C)c1cc(C(F)(F)F)cc(C(F)(F)F)n1)C(C)C

Procedure:
A solution of 1-[4,6-bis[trifluoromethyl]pyrid-2-yl]-1-methyl hydrazine (40.04 g; 0.15 mol), 3-methyl-2-butanone (14.2 g; 0.165 mol) and p-toluenesulphonic acid (0.32 g) in toluene (90 ml) was heated under reflux, with water removal (azeotrope), for 40 h. The solution was concentrated to yield a dark oil which was purified by flash-chromatography over silica (eluent: petroleum ether 60/80) to yield 3-methyl-2-butanone 1-[4,6-bis[trifluoromethyl]pyrid-2-yl]-1-methyl hydrazone as a red oil (10.9 g; 22%). ##STR26##