Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([OH:14])[C@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O[C@H]1OCCN(Cc2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 3.72 g (13.9 mmol) of 4-benzyl-3-(R)-phenyl-2-morpholinone, prepared from (R)-phenyl-glycine as described in Example 14, in 28 mL of CH2Cl2 was cooled in a -78° C. bath under a N2 atmosphere and 14 mL of a 1.5M solution of DIBAL-H (21 mmol) in toluene were added. After stirring the resulting solution for 0.5 h, it was allowed to warm to -50° C. and mantained at this temperature for 0.5 h. The reaction mixture was quenched by adding 10 mL of aqueous potassium sodium tartarate. The mixture was diluted with CH2Cl2 and the layers were separated. The aqueous layer was extracted 3 times with CH2Cl2. The CH2Cl2 layers were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate furnished 3.32 g (88%) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine suitable for use in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[N:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.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>[C:30]([C:25]1[CH:24]=[C:23]([C:14]2[N:15]=[C:16]([C:18]([OH:20])=[O:19])[S:17][C:13]=2[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[CH:28]=[CH:27][C:26]=1[F:29])#[N:31]
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Reactant: N#Cc1cccc(B(O)O)c1
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: COCCOC
Product: N#Cc1cccc(-c2sc(C(=O)O)nc2-c2ccc(F)c(C#N)c2)c1

Procedure:
At room temperature, 217 mg (1.48 mmol) of (3-cyanophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 2 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 47.3 mg (14% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1)#[N:19]>CCOC(C)=O>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][C:15](=[O:17])[CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: N#Cc1ccc(CCN)cc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(ncn2CC(=O)NCCc2ccc(C#N)cc2)n(C)c1=O
Yield: 21.2 %

Procedure:
Compound 409 (93 mg, 21%) was prepared from 101 (300 mg, 1.3 mmol) and 115 (175 mg, 1.2 mmol) according to General Procedure B. MS (APCI): m/z 367 [M+H]+. Anal. Calcd. for C18H18N6O3.0.04 EtOAc.0.1H2O: C, 58.68; H, 5.02; N, 22.61. Found: C, 58.75; H, 5.01; N, 22.46.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH3:12])[CH:5]=1>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(O[C@H](C)C(=O)OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc(O[C@H](C)C(=O)O)c1
Reaction time: 2 h
Yield: 74.3 %

Procedure:
Add palladium hydroxide (3.0 g, 21 mmol) to a solution of 3-((R)-1-benzyloxycarbonyl-ethoxy)-benzoic acid methyl ester (14 g, 45 mmol) in MeOH (400 mL). De-gas the mixture with Argon for 10 minutes then place under 60 psi of hydrogen. Shake the vessel for 2 hours. Filter the mixture through a pad of diatomaceous earth and concentrate under reduced pressure. Triturate the residue with a mixture of hexanes and methylene chloride to provide 7.5 g of 3-((R)-1-carboxy-ethoxy)-benzoic acid methyl ester as a solid.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1.C[O-].[Na+]>CO>[CH2:9]([C@@H:8]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[O:14])[C@H:4]([OH:3])[C:5]([O:6][CH3:2])=[O:7])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C1OC(C)(C)OC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](O)C(=O)OC
Reaction time: 1 h

Procedure:
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)pentane G-2 (5 mmol, 50%) (5 mmol) in methanol (20 mL) was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stirred for 1 hour. Amberlite IR-120 resin (H+ form) was added, then the solution was filtered and concentrated to afford methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-hydroxypropionate G-3 (quant.).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=1)[C:20](=[O:30])[CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=1)[C:20](=[O:30])[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CCC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CCC(=O)O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from example 18 (140 mg) was dissolved in DCM (1 ml) and TFA (0.2 ml) added. The mixture was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 solution and dried. The mixture was purified by RPHPLC, which afforded the title compound. Yield 80 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34]CC)=[O:33])=[C:12]2[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:46])([F:45])[F:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([OH:34])=[O:33])=[C:12]2[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:45])([F:46])[F:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccccc2C(F)(F)F)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2C(F)(F)F)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 135B (30 mg), 2-(trifluoromethyl)phenylboronic acid (15.3 mg), tetrakis(triphenylphosphine)palladium(0) (3.1 mg) and cesium fluoride (16.3 mg) in dimethoxyethane (1.4 ml) and methanol (0.7 ml) was heated at 100° C. in a microwave reactor (CEM Discover) for 30 minutes and was concentrated. The residue was purified by flash chromatography, eluting with 0%-100% dichloromethane in hexane, to provide ethyl 5-(benzyloxy)-1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J=7.32 Hz, 1H), 7.82 (d, J=7.63 Hz, 1H), 7.69 (t, J=7.32 Hz, 1H), 7.57-7.65 (m, 2H), 7.44-7.56 (m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J=9.00, 2.29 Hz, 1H), 6.85 (d, J=7.93 Hz, 1H), 6.55 (d, J=2.14 Hz, 1H), 4.83-4.98 (m, 4H), 4.05-4.24 (m, 2H), 2.28-2.40 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#N.CN.C(OC)(=O)C1[C:17](=CC=CC=1)[NH2:18]>C(O)C>[NH2:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:18][CH:17]=[CH:4]2
Reactant: COC(=O)c1ccccc1N
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: CN
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1

Procedure:
Compound 245 was prepared using methods shown in Example 1, wherein 2-fluoro-5-nitrobenzonitrile and methylamine were used in Step A and methyl anthranilate was used in Step D. Reduction of the 5-nitro group was carried out using stannous chloride in ethanol to provide the corresponding 5-amino indole intermediate. Dimethylation of the 5-amino group was carried out using aqueous formaldehyde solution (37% w/w, 10 eq.) and MP-cyanoborohydride resion (2.42 mmol/g, 1.5 eq.) in methanol:acetic acid (9:1, v/v) at room temperature for about 15 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:5]=[O:6]
Reactant: BrC1CCCCC1
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCCC2)c(Br)c1
Temperature: 90 °C
Yield: 38.4 %

Procedure:
3-Bromo-4-hydroxy-benzaldehyde (24.8 mmol, 5.0 g), bromo-cyclohexane (37.3 mmol, 6.08 g) and K2CO3 (37.3 mmol, 5.15 g) were suspended in DMF (15 mL) and stirred over night at 90° C. The mixture was cooled to room temperature, and bromo-cyclohexane (36.8 mmol, 6.0 g) and K2CO3 (36.2 mmol, 5.0 g) were added stirred at 90° C. for another 24 h. The mixture was cooled and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with 1.0 N NaOH (200 mL), water, and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide 3-bromo-4-cyclohexyloxy-benzaldehyde (2.7 g).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:14][CH3:15])(=O)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-].[Cs+].[Cs+]>N1C=CC=CC=1.[Cu]=O>[OH:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH:9]=[O:10])=[C:11]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[CH:12]=1
Reactant: COc1c(OC(C)=O)ccc(C=O)c1Br
Reactant: COc1ccccc1O
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: COc1cc(C=O)c(Oc2ccccc2OC)cc1O
Temperature: 130 °C

Procedure:
To a mixture of 4-acetoxy-2-bromo-3-methoxybenzaldehyde (546 mg, 2 mmol; prepared in example 105, step a), 2-methoxy-phenol (280 mg, 2 mmol) and cesium carbonate (1.3 g, 4 mmol) in 16 mL of pyridine was added copper oxide(320 mg, 4 mmol)under argon. The mixture was purged with argon for 10 min, heated at 130° C. overnight and then quenched with 5% HCl solution. The mixture was extracted with ethyl acetate, washed with 1N NaOH solution and water before drying over sodium sulfate. After the removal of the solvent, the residue was chromatographed to give the product, 4-hydroxy-5-methoxy-2-(2-methoxy-phenoxy)-benzaldehyde.
Reaction SMILES: [N:1]([C@H:4]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH:31]([CH3:33])[CH3:32])[CH2:26]1)[CH2:5][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:12]=1)[CH:7]([CH3:9])[CH3:8])=[N+]=[N-].[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:35]1([NH:34][C:28](=[O:30])[C@H:27]([CH:31]([CH3:33])[CH3:32])[CH2:26][C@H:25]([OH:29])[C@@H:4]([NH2:1])[CH2:5][C@H:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:12]=2)[CH:7]([CH3:9])[CH3:8])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OC
Reactant: Nc1ccccc1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)Nc2ccccc2)C(C)C)C(C)C)ccc1OC

Procedure:
Analogously to Method C, 0.466 g of 5(S)-{1(S)-azido-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}-3(S)-isopropyidihydrofuran-2-one [324763-46-4] and 0.11 ml of aniline are reacted. The title compound is obtained as a colourless oil. Rf=0.53 (2:1 EtOAc-heptane); Rt=5.41 minutes (gradient I).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:32](=[O:33])[CH2:31][O:30][CH3:29])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.319 g, 1.1 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (1.0 mL, 7 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Methoxyacetyl chloride (460 μm, 5.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). The UV absorbing eluent was concentrated and separated on a Chromatotron (4 mm silica gel plate) with a mixture of chloroform:acetone (95:5). Solvents were removed in vacuo and the residue was further purified on a preparative silica gel plate (20×20×0.2 cm) developed in a mixture of chloroform:acetone (70:30). The product was scraped from the preparative plate and eluted from the silica gel with ethanol. Lyophilization afforded 0.217 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(methoxyacetoxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (53% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([Cl:21])[C:14]=1[OH:22].N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:12][C:13]1[CH:18]=[C:17]([CH:16]=[C:15]([Cl:21])[C:14]=1[O:22][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:19][OH:20]
Reactant: COc1ccc(B(O)O)cc1
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a flask containing 24 ml of dichloromethane was added 4 A sieves (2.97 g, activated at 500° C. for 8 h), 4-methoxyphenylboronic acid (1.84 g, 12.0 mmol), 2,6-dichloro-4-hydroxymethylphenol (465 mg, 2.41 mmol), copper (II) acetate (438 mg, 2.41 mmol), pyridine (0.97 ml, 12.0 mmol) and triethylamine (1.67 ml, 12.0 mmol). The reaction flask was fitted with a drying tube and stirred overnight. Filtration through celite and removal of volatiles in vacuo followed by column chromatography (silica, 30% ethyl acetate in hexane) provided the title compound as light brown oil (323 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 6.82 (d, j=7.2 Hz, 2H), 6.77 (d, j=7.2 Hz, 2H), 4.69 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.[ClH:19]>CO.O1CCOCC1.[Pd]>[ClH:19].[F:16][C:15]([F:17])([F:18])[CH:12]1[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1
Reactant: FC(F)(F)C1CCC(NCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCC(C(F)(F)F)CC1

Procedure:
A solution of benzyl(4-trifluoromethylcyclohexyl)amine (Preparation 4) (1.48 g, 5.73 mmol) in MeOH (150 mL) was passed through an H-Cube at 100° C. fitted with a 10% Pd/C CatCart and on full H2 mode. The volume was reduced to 50 mL and 4M HCl in dioxane (1.43 mL) was added. The precipitate was filtered, the filtrate collected and the solvent removed in vacuo. The resulting residue was triturated with acetone to give the title compound: δH (CD3OD) 1.41-1.53 (4H, m), 2.03-2.25 (5H, m), 3.07-3.15 (1H, m).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 2.748 g (7.28 mmol) of the phthalimide prepared above and 398 microliters (8.0 mmol) of 98% hydrazine hydrate in 75 ml of ethanol is heated overnight at reflux under N2. After cooling to RT, the volatiles are removed under vacuum. The residual white solid is taken up in 15 ml of 70:30 CH3OH:NH4OH and flash chromatographed on silica gel (90:10:2 CHCl3 :CH3OH:NH4OH) to give 929 mg of 6-[4-(3-aminopropyloxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 23%.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.O>C1COCC1>[Cl:18][CH2:19][CH2:20][CH2:21][N:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:8](=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccc(NCCCCl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N(CCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.[I-].[Na+]>O1CCCC1.C1C=CC=CC=1.C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:5]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]=1[O:13][CH3:14]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: BrCCCCCCCBr
Agent: [I-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COCOc1cc(OC)c(OCOC)c(CCCCCCCBr)c1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
5 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 140 ml of tetrahydrofuran, then the solution was cooled to -78° C. under argon gas stream condition, in a dry ice-acetone bath. Then 18 ml of sec-butyllithium (1.3 mole cyclohexane solution) was added dropwise thereto and stirred for 30 minutes. To the reaction mixture was added dropwise 10 g (6.7 ml) of 1,7-dibromoheptane, next 6 g of sodium iodide and 10 ml of hexamethylphosphoric triamide were added to the reaction mixture. The cooling bath was removed from the reaction apparatus, and the reaction mixture was stirred at room temperature for 12-14 hours. Tetrahydrofuran was removed by evaporation under reduced pressure, the residue obtained was dissolved in 500 ml of a mixed solvent benzene-diethyl ether (1:1). The organic layer was washed with 100 ml of water in 4 times, and with 100 ml of saturated sodium chloride aqueous solution in 4 times, and dried over anhydrous magnesium sulfate. After the removal of the solvent by evaporating under reduced pressure, the residue obtained was treated by means of a silica gel column chromatography (diameter 5 cm×length 30 cm, adsorbent: "Wakol-C200") and developed and eluted with 20%-ethyl acetate-n-hexane to obtain 6.06 g (yield=72%) of 1-bromo-7-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]heptane. Colorless oily substance.