Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH2:25][C:26]#[C:27][CH3:28])[C:20]([N:29]3[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30]3)=[N:19][C:18]=2[N:17]([CH3:43])[C:15]1=[O:16].C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]([CH2:44][O:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH2:25][C:26]#[C:27][CH3:28])[C:20]([N:29]3[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:30]3)=[N:19][C:18]=2[N:17]([CH3:43])[C:15]1=[O:16]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(O)COc1ccccc1)c(=O)n2C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)COc1ccccc1)c(=O)n2C
Temperature: -60 °C

Procedure:
A solution of 107 μl dimethylsulphoxide in 0.5 ml methylene chloride is added dropwise to 64 μl oxalyl chloride in 2 ml methylene chloride with stirring at −60° C. After five minutes a solution of 345 mg of 1-(2-hydroxy-3-phenoxy-propyl)-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 1.5 ml methylene chloride is added dropwise and after another 15 minutes 0.42 ml of triethylamine are added. Then the cooling bath is removed and the reaction mixture is allowed to warm up to ambient temperature. For working up it is diluted with methylene chloride and washed with water. The organic phase is dried over magnesium sulphate, evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (4:1 to 1:1) as eluant.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:27]=[CH:26]C(C#N)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:28].[C:29]([OH:32])(=[O:31])[CH3:30]>O>[ClH:28].[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:27]=[CH:26][C:30]([C:29]([OH:32])=[O:31])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(N2CCN(c3ccc(C#N)cc3)CC2)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A solution of 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]-benzonitrile (0.582 g) in the mixture of conc. HCl (5.8 ml) and acetic acid (2.9 ml) was refluxed for 3 hours. The reaction mixture was pulverized with water (25 ml). The precipitate was collected by filtration to give 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (0.51 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[C:6]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:8]#[N:9].[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:22][CH2:21]1)(=O)[CH3:18].ClCCl.N>CO>[CH:11]1([O:10][C:6]2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=[C:2]([N:1]=[C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])[CH2:22][CH2:21]3)[CH3:18])[C:7]=2[C:8]#[N:9])[CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OC2CCC2)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OC2CCC2)c1

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-cyclobutyloxyanisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 14(d) (93%). Rf 0.52 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). MS m/z 456 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8].[CH3:30][O:31][CH2:32][CH2:33][CH2:34][NH2:35].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]=O.CC(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([NH:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30])[N:24]=4)=[O:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8]
Reactant: COCCCN
Reactant: O=C(NC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)n1)(C3)C2)c1ccccn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCNc1cccc(C(=O)NC23CC4CC(CC(NC(=O)c5ccccn5)(C4)C2)C3)n1
Temperature: 230 °C

Procedure:
To a microwave vial was added a stir bar, 6-chloro-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide (Intermediate 4, 20 mg, 0.05 mmol), copper (II) oxide (20 mg, 0.2 mmole), DMA (1 mL), 3-methoxy-propylamine (0.05 mL) and cesium carbonate (120 mg, 0.3 mmol). The mixture was heated at 230° C. under microwave irradiation for 30 min. Solvent was removed in Genevac. The residue was dissolved in DCM (2 mL), washed with aq. 1 N NaOH (2 mL), and water (2×2 mL). After removing the solvent, the crude product was purified on a RP-HPLC/MS system (Gradient: acetonitrile in water with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium acetate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 3.9 mg of the title compound, 6-(3-methoxy-propylamino)-pyridine-2-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-1-yl}-amide. The product was quality checked (QC) by LC-MS (Gradient: acetonitrile in water, 30-90%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® C8, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 1.29 min; purity (UV254): 94%; ESI-MS m/z: 464.6 (M+H)+.
Reaction SMILES: N1C=CN=C1.[I:6]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:27][C@@H:28]([CH2:38]O)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[F:27][C@@H:28]([CH2:38][I:6])[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@@H](F)CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](F)CI
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Imidazole (26.6 g, 0.39 mol) was dissolved in methylene chloride (400 mL) at room temperature. Iodine (102.5 g, 0.39 mol) was added and the reaction mixture was stirred for 10 min at room temperature and then cooled to 0° C. Triphenylphosphine (102.5 g, 0.39 mol) was added portionwise over 10 min such that the internal temperature remained below 10° C. A solution of tert-butyl (2R)-2-fluoro-3-hydroxypropylcarbamate (60.4 g, 0.31 mol) in methylene chloride (100 mL) was added dropwise. On completion of addition of tert-butyl (2R)-2-fluoro-3-hydroxypropylcarbamate, additional methylene chloride (200 mL) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued for 17 h. The reaction mixture was filtered through a pad of Celite® (50 g) and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with methylene chloride. This procedure afforded tert-butyl (2R)-2-fluoro-3-iodopropylcarbamate as a white solid (64.7 g, 68%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][CH:16]([P:20]([CH3:25])(=[O:24])[O:21][CH2:22][CH3:23])[O:17][CH2:18][CH3:19])[CH3:14].[N+:26]([CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O-:28])=[O:27].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N+:26]([CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:25][P:20]([CH:16]([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])(=[O:24])[O:21][CH2:22][CH3:23])([O-:28])=[O:27]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CCOC(OCC)P(C)(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccccc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 5.8 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 35.7 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 10.0 g of ethyl (diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 8.5 g of β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 3-nitro-2-phenylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+42.4 and +42.0 ppm (CDCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].[CH3:14]O>>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
(2-Nitro-phenyl)-acetic acid (10.93 g, 60.3 mmol) is dissolved in MeOH (200 mL) and HCl gas is bubbled through the solution for 10 min. The reaction is stirred capped for 18 h, then concentrated under reduced pressure to yield (2-nitro-phenyl)-acetic acid methyl ester as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[O:8])[CH2:3][CH2:2]1.[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30]([N:1]3[CH2:2][CH2:3][CH:4]([C:7](=[O:8])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:16])([F:17])[F:18])[CH2:5][CH2:6]3)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1
Reactant: O=C(c1ccccc1C(F)(F)F)C1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use piperidin-4-yl-(2-trifluoromethylphenyl)methanone in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 42% yield. 1H NMR (300 MHz, CDCl3) δ 8.0 (d, J=10.0 Hz, 1H), 7.99 (m, 1H), 7.72 (m, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 6.97 (d, J=10.0 Hz, 1H), 4.49 (m, 2H), 3.53 (q, J=7.0 Hz, 2H), 3.24-3.07 (m, 4H), 2.1-1.9 (m, 3H), 1.85-1.65 (m, 2H), 1.5 (q, J=7.0 Hz, 2H), 0.75 (m, 1H), 0.48-0.42 (m, 2H), 0.09-0.07 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 205.3, 174.6, 163.2, 159.9, 144.6, 138.9, 130.3, 128.9, 127.5, 127.1, 127.0, 121.7, 112.2, 65.8, 51.9, 48.0, 44.5, 39.6, 34.5, 27.1, 8.6, 4.2. MS (ES+) m/z 447.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])=[C:3]([F:17])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)c(F)c1
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxyphenylboronic acid.
Reaction SMILES: I(C1C=CC=CC=1)=O.B(F)(F)F.[CH3:13][CH2:14][O:15]CC.[CH2:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][Si](C)(C)C)=[CH2:27])=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20]>C(O)C>[CH2:18]([C:22]1[CH:34]=[CH:33][C:25]([C:26](=[O:27])[CH2:28][O:15][CH2:14][CH3:13])=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CCOCC
Reactant: C=C(O[Si](C)(C)C)c1ccc(CC(C)C)cc1
Agent: FB(F)F
Agent: O=Ic1ccccc1
Solvent: CCO
Product: CCOCC(=O)c1ccc(CC(C)C)cc1
Temperature: -70 °C
Yield: 95.7 %

Procedure:
Iodosylbenzene (2.18 g) was dissolved in ethanol (45 ml), and boron trifluoride etherate (2.55 g) was added. The mixture was stirred at -70° C., and then 4-isobutyl-α-trimethylsilyloxystyrene (2.24 g) was added. The mixture was stirred at -70° C. for 30 minutes, and then the temperature was slowly raised to room temperature. The ethanol was evaporated and water was added. The mixture was neutralized with aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel column eluting with hexane-ethyl acetate (94:6) to give 4'-isobutyl-2-ethoxyacetophenone (1.90 g) as an oil.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCl
Reactant: COc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OCCC(=O)O)cc1
Yield: 18.1 %

Procedure:
Solid KOH (6.80 g, 0.122 mol) and H2O (10 mL) are added to 4-methoxyphenol (7.0 g, 0.0564 mol), the resultant mixture is stirred at the room temperature while 3-chloropropanoic acid (6.12 g, 0.0564 mol) is added to thereof. Then the mixture is stirred and heated to reflux for 3 h. The mixture is acidified to pH 2 by adding concentrated aqueous HCl and extracted with ether. The combined ether extracts is then washed by 10% aqueous NaHCO3 and acidified to pH 3-4 by adding concentrated aqueous HCl, and precipitate was formed. The residue is filtered and recrystallized by benzene to provide needle crystal 2.0 g. m.p.: 102-103° C., yield: 18.1%.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:42]1([C:48]2[O:49][C:50]3[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:51]=3[CH:52]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.C(OCC)(=O)C>[C:42]1([C:48]2[O:49][C:50]3[CH:56]=[CH:55][C:54]([NH:57][C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])=[CH:53][C:51]=3[CH:52]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Nc1ccc2oc(-c3ccccc3)cc2c1
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)Nc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
To 3,3,3-trifluoropropanoic acid (136 mg, 1.06 mmol) in dry dichloromethane (10 mL) was added HATU (468 mg, 1.23 mmol) and diisopropylethylamine (580 μL, 3.35 mmol). The mixture was then stirred at room temperature for 10 min. 2-phenylbenzofuran-5-amine (234 mg, 1.12 mmol) was then added and the resulting mixture was stirred at room temperature for 48 h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:1 v/v) followed by trituration in ethyl acetate to afford 99.3 mg (28%) of the title compound (LCMS RT=6.62 min)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>CS(C)=O.C(OCC)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:22][CH2:21]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Reactant: CN
Solvent: CCOCC
Solvent: CS(C)=O
Product: CNCC1CCc2cccc(-c3ccccc3Cl)c2O1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
To a suspension of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.30 mmol) in dimethylsulfoxide (0.5 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 1.5 mL, 3.0 mmol) and the mixture heated to 60° C. in a sealed vial for 24 hours. The cooled reaction mixture was then diluted with diethyl ether (10 mL), washed with water (5×5 mL) and saturated brine (5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave 69 mg (79%) of N-{[8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}-N-methylamine. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (3 drops). The resulting white precipitate was filtered to afford 74 mg (76%) of N-{[8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}-N-methylamine hydrochloride as a white solid. HRMS: calcd for C17H18ClNO+H+, 288.11497. found (ESI, [M+H]+), 288.1143.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8](Cl)[N:7]=[CH:6][N:5]=2.C(N(C(C)C)CC)(C)C.Cl.[C:23]([C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)#[N:24]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8]([N:28]1[CH2:27][CH2:26][C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:23]#[N:24])[CH2:30][CH2:29]1)[N:7]=[CH:6][N:5]=2
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Cn1c(Br)nc2c(Cl)ncnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Br)nc2c(N3CCC(C#N)(c4ccccc4)CC3)ncnc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
8-bromo-6-chloro-9-methyl-9H-purine (200 mg, 0.80 mmol) was dissolved in DMF (4 mL). To this solution was added diisopropylethylamine (0.21 mL, 1.21 mmol). To this stirred mixture was added 4-cyano-4-phenylpiperidine hydrochloride (165 mg, 0.88 mmol) dissolved in a small amount of DMF. The resulting mixture was heated to 70° C. and stirred for 30 minutes. The solvent was removed in vacuo and the crude material was used without purification.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH2:2].[OH-].[Na+].[CH3:27]I>>[CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:27])=[CH2:2]
Reactant: CI
Reactant: C=COCCOCCOCCOCCOCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Product: C=COCCOCCOCCOCCOCCOCCOCCOC
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A 1-L flask equipped with a stirrer, a dropping funnel, a thermometer, a condenser tube, and a nitrogen gas inlet was charged with 50 parts of heptaethylene glycol vinyl ether and 11 parts of sodium hydroxide. The flask was heated to 40° C. with stirring under a nitrogen atmosphere, and then 40 parts of methyl iodide was slowly dropped while the internal temperature was maintained at 40° C. or lower. After completion of the dropping, the mixture was aged for five hours, and distilled under reduced pressure so that unreacted methyl iodide was removed. In order to further remove sodium hydroxide in excess and water and sodium iodide generated after the reaction, adsorption treatment was performed using an adsorbent, and thereby heptaethylene glycol methyl vinyl ether was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][N:19]1[C:23]([CH3:24])=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]([CH3:34])=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[C:21]([CH3:34])=[N:20][N:19]([CH3:18])[C:23]=2[CH3:24])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
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: CC#N
Product: Cc1nn(C)c(C)c1-c1cncc(Cl)c1N1CCC(C(N)=O)CC1

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic pinacol ester (65 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 94:6-80:20, biotage 25+S) to furnish the title compound as a very pale yellow solid (34 mg, 35%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (52 mg, 57% RSM), LC-MS (ESI, 4 min) Rt 1.55 min, m/z 348 (100%, [M+H]+); m/z (ESI) C17H22N5OCl requires 347.1513, found [M+H]+ 347.1508.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:13]([Mg]Cl)([CH3:15])[CH3:14]>C1COCC1>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([OH:8])[CH:13]([CH3:15])[CH3:14])[CH:9]=1
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc(O)c(C=O)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(O)c(C(O)C(C)C)cc1Cl
Reaction time: 0.5 h

Procedure:
The above prepared 5-chloro-2-hydroxy-4-methoxy-benzaldehyde (0.845 g, 4.53 mmol) was dissolved in 10 mL of abs. THF and treated at −15° C. with iPrMgCl (4.98 mL of 2M [THF], 2.2 eq.) and the mixture kept at this temperature for 0.5 h. Careful pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 1.090 g of the title compound as light brown oil, almost perfectly pure according to TLC and NMR.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH:2]=CC1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>>[C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH3:2]
Reactant: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(N)c(Br)c2)c1Cl
Reactant: CC(C)C(=O)Cl
Product: CCc1c(OC(C)=O)cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(Br)c2)c1Cl
Yield: 103.7 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) cinnamate (70 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 70 mg of ethyl(3,5-dichloro-4-[3-bromo-4-isobutyramidophenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 50 mg of 3,5-dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenylacetic acid.