Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCC.[CH2:5]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[C:6]#[CH:7].[F:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=[O:23])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:5][C:6]#[C:7][CH:22]([OH:23])[CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([F:15])=[CH:17][CH:18]=1
Reactant: C#CCOC1CCCCO1
Reactant: O=CCOc1ccc(F)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCBr
Product: OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the Grignard reagent prepared from magnesium (12.2 g., 0.5 mole) and bromoethane (54.5 g., 0.5 mole) in tetrahydrofuran (400 ml.) is added, dropwise, during 30 minutes, a solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (67.3 g., 0.5 mole) in tetrahydrofuran (50 ml.). The mixture is stirred at room temperature for 1 hour and then treated, dropwise, during 1 hour with 4-fluorophenoxyacetaldehyde (61.6 g., 0.4 mole). The resulting mixture is heated at reflux for 1 hour, then cooled and poured into an ice-cold saturated solution of ammonium chloride in water.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:23]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cccnc2c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-hydroxyquinoline (2.240 g, 15.43 mmol) in dry CH2Cl2 (30 mL) were added (in this order) DMAP (94 mg, 0.77 mmol), triethylamine (4.3 mL, 3.1 g, 31 mmol), and TBDMSCl (2.558 g, 16.97 mmol), and the mixture was stirred overnight at ambient temperature. Water and sat. NH4Cl sol. (10 mL each) were added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with 0.25 M citric acid (2×), water, sat. NaHCO3 solution, and brine, and dried over MgSO4. EtOAc (10 mL) was added to the solution, which was then filtered through a silica gel plug (60 mL glass frit filled ≈½ with silica gel) and concentrated to give the title compound as pale yellow oil. The material thus obtained was used without further purification; 1H NMR (CDCl3, 400 MHz) δ 0.29 (s, 6H), 1.03 (s, 9H), 7.15 (dd, J=2.8, 8.8 Hz, 1H), 7.26 (dd, J=4.0, 8.0 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 8.08 (dd, J=0.8, 8.0 Hz, 1H), 8.83 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 260.2 (100) [MH+]; HPLC: tR=3.8 min (OpenLynx, polar 5 min).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:8]=[C:7]1SC.[C:30]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11](=[O:12])[N:6]3[CH:5]=[C:4]([CH3:3])[N:39]([CH2:38][CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:7]3=[N:8][C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCCc1ccccc1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1CC#C[Si](C)(C)C
Product: Cc1cn2c(=O)c(-c3ccc(F)cc3)c(-c3ccncc3)nc2n1CCCc1ccccc1
Temperature: 190 °C

Procedure:
A neat mixture of 3-(3-trimethylsilyl-2-propynyl)-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (50 mg, 0.12 mmol) and 3-phenyl-1-propylamine (67 mg, 0.47 mmol) was warmed to 190° C. for 17 h. After cooling to 23° C., the reaction mixture was applied directly to purification via flash chromatography (step gradient 1% MeOH:CHCl3 then 2%, then 3%;) to afford the desired product: MS (m/z) 439 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12.O1CCOCC1.[NH:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]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.O>[Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:41]4[CH:42]=[N:38][NH:39][CH:40]=4)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12
Reactant: OB(O)c1cn[nH]c1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(I)ccc32)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]c4)ccc32)c1Br
Yield: 44 %

Procedure:
342 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline are introduced into 13 ml of 1,4-dioxane. 74 mg of 4-pyrazoleboronic acid, 77 mg of Pd(PPh3)4 and 165 mg of sodium carbonate are added. The mixture is heated at reflux for 4 h 30 min. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/05 by vol.), to give 136 mg of 3-bromo-5-(2,6-difluorophenyl)-7-(1H-pyrazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white foam), which is used as it is in the following step.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:9]
Reactant: CCOC(=O)Cn1nccc1-c1ncccc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nccc1-c1ncccc1COc1cnc(OC)cc1C=O
Temperature: 70 °C
Yield: 94.1 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (107 mg, 0.70 mmol, 1 eq.), ethyl 2-(5-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate hydrochloride (220 mg, 0.70 mmol, 1 eq.), and K2CO3 (386 mg, 2.8 mmol, 4 eq.) in DMF (6.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give ethyl 2-(5-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)acetate (261 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.69 (d, J=3.8 Hz, 1H), 8.02 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.40 (dd, J=7.6, 4.0 Hz, 1H), 7.13 (s, 1H), 6.53 (d, J=1.6 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 1.18 (t, J=7.1 Hz, 3H). LRMS (M+H+) m/z 397.1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.C([NH:34][CH2:35][CH2:36][OH:37])C1C=CC=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:34][CH2:35][CH2:36][OH:37])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Reactant: OCCNCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCNCCO)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with 2-(benzylamino)ethanol, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.79 (2H, t), 3.17 (2H, t), 3.55 (2H, t), 4.20 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.17 min; m/z (ES+) 404.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=[O:15])=[O:4].[O-:16]Cl=O.[Na+].OO.Cl>C(#N)C.CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=[O:15])=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(C=O)c2c1
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]nc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
To a solution of 5 g 3-Formyl-1H-indazole-5-carboxylic acid methyl ester in 100 mL acetonitrile and 8 mL DMF a solution of 4.4 g NaH2PO4 in 90 mL water was added dropwise at RT within 1 h. Then a solution of 4.2 g NaClO2 (80%) in 90 mL water followed by 5.3 mL H2O2 (30%) was added dropwise at 0° C. After stirring for 16 h at RT the reaction mixture was cooled to 0° C. followed by addition of 180 mL half-concentrated aqueous hydrochloric acid. The precipitated product was collected by filtration to yield 2.3 g pure product. The filtrate was extracted with ethyl acetate (3×150 mL), the combined organic layers were dried over MgSO4. After removal of the solvent under reduced pressure further 3.42 g of product were obtained. The combined product fractions were used without further purification. Yield: 5.7 g.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].S(Cl)([Cl:16])=O>>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: N=C(N)Nc1ccc(C(=O)Cl)cc1

Procedure:
5.4 g of 4-guanidinobenzoic acid and 50 ml of thionyl chloride were heated at 70° to 75° C. for 30 minutes with stirring. To the reaction mixture was added petroleum ether to precipitate crystals of 4-guanidinobenzoyl chloride hydrochloride, which were filtered and washed with petroleum ether. The 4-guanidinobenzoyl chloride, thus obtained, was added to 7.9 g of piperidinocarbonylmethyl 4-hydroxybenzoate in 100 ml of pyridine at 0° C., followed by stirring at 10° to 20° C. for 3 hours. To the reaction mixture was added diethyl ether, and the supernatant was removed by decantation, and then to the residual oil was added a saturated aqueous solution of sodium bicarbonate. The precipitated crystals were filtered off, washed successively with water and acetone, and dried. The obtained crystals were suspended in methanol, and the suspension was acidified at pH 3 by adding methanesulfonic acid, and then filtered. Diethyl ether was added to the filtrate to precipitate crystals. Recrystallization thereof from methanol afforded 8.4 g (70%) of the title compound as white crystals. Melting point: 189°-190° C.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=CC=1>CCOC(C)=O.O>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:33][CH2:34]1
Reactant: CN1CCC(Oc2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenoxy)-1-methylpiperidine (300 mg, 1.11 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give the crude product. Crude product was purified by flash chromatography using MeOH/CH2Cl2 (2:98 to 15:85) to give the title compound as a brown solid (200 mg, 57%). 1H NMR (400 MHz, CD3OD) δ 7.68 (d, J=7.6 Hz, 2H), 6.94 (d, J=7.7 Hz, 2H), 4.53 (br s, 1H), 2.94-2.91 (m, 2H), 2.58-2.50 (m, 2H), 2.40 (s, 3H), 2.18-2.00 (m, 2H), 1.93-1.78 (m, 2H), 1.34 (m, 12H); MS ESI 318.1 [M+H]+, calcd for [C18H28BNO3+H]+ 318.22.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>ClCCl.CCN(CC)CC>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:15]
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2cnccc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.1 %

Procedure:
A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane (40 mL) and Et3N (1 mL) at 5° C. was treated with trichloroacetyl chloride (1.38 g, 7.6 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, concentrated, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was treated with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer the was washed with water and concentrated. The solid residue was suspended in ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 11.20 (broad s, 1H), 9.41, (s, 1H), 8.60 (d, 1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.66 (d, 1H); MS (DCI/NH3) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:31]([C:33](O)=[O:34])[N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[CH2:26][CH2:27][C:28]1[O:29][C:30]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:31]([C:33](=[O:34])[NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[N:14]=2)[N:32]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)(C)OC(=O)CCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(CCC(=O)OC(C)(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-(2-tert-butoxycarbonyl-ethyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.09 min; [M+H]+=505.42.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1C(NCC1CCCCN1)=O.BrC1C=CC(Br)=CC=1.FC(F)(F)CO>>[F:1][C:2]([F:27])([F:28])[CH2:3][O:4][C:5]1[CH:6]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=1
Reactant: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: Brc1ccc(Br)cc1
Solvent: OCC(F)(F)F
Product: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1

Procedure:
In yet another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. The compound 1,4-dibromobenzene is contacted with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Subsequently, the 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Finally, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)[CH2:4][CH3:5].S(C1C=CC(C)=CC=1)(O[CH2:15][C@@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[NH:23][CH:22]=3)[N:18]([CH3:32])[CH2:17]1)(=O)=O>CN(C)C=O>[CH3:32][N:18]1[C@H:19]2[C@@H:29]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:31]=3[C:21]([CH2:20]2)=[CH:22][NH:23]4)[CH2:30][C@@H:16]([CH2:15][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH2:3][CH2:4][CH3:5])[CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
0.68 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.1 g of 2-propylimidazole and 50 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (eluted with ethyl acetate:benzene=1:2, and then with ethyl acetate). The resulting product was recrystallized from acetone-hexane to obtain 0.8 g of the titled compound as colorless needles having a melting point of 223°-227° C. (with decomposition).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CN1CCOCC1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[C:17](=[O:18])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(O)CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 4-hydroxy-1-methyl piperidine (3.00 g, 26.1 mmol) and NMM (3.0 mL, 27.3 mmol) in DCM (50 mL) at 0° C. was added p-nitrophenyl chloroformate (5.51 g, 27.4 mmol). The reaction mixture was stirred at room temperature for 4 hours, and a cream precipitate gradually formed. The reaction mixture was filtered and the residue was washed with DCM (50 mL) to give 1-methylpiperidin-4-yl 4-nitrophenyl carbonate (7.24 g, 99%) as a cream solid.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13]C[C:11](=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:16]([OH:22])([C:18](F)(F)F)=O.[CH3:23]C(C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:23][CH:14]([N:8]1[CH2:9][CH2:10][CH2:11][C:16](=[O:22])[CH2:18][CH2:1]1)[CH3:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCCC(=O)CC1
Reaction time: 2 h

Procedure:
N-Boc-hexahydro-1H-azepine-4-one (3.00 g, 14.1 mmol) was dissolved in DCM (50 mL), TFA (15 mL) was added and the reaction mixture was stirred for 2 h. The solvents were removed in vacuo and the residue partitioned between DCM (500 mL) and sat aq Na2CO3 (500 mL). The aq fraction was extracted with DCM (2×250 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and acetone (10 mL) and NaBH(OAc)3 (2.18 g, 141 mmol) were added. The reaction mixture was stirred for 18 h, diluted with DCM (200 mL) and quenched with sat aq Na2CO3 (150 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the crude title compound (2.18 g) as a brown liquid. LCMS (ES+): 156.2 [MH]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][NH2:17])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2].C(N(CC)CC)C.O.[O:40]1CCC[CH2:41]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[O:15][C:41](=[O:40])[NH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
72 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carbohydrazide (compound 133) was dissolved in 4 mL of tetrahydrofuran, and 55 mg of N,N′-carbonyldiimidazole and 47 μL of triethylamine were added to the solution. The mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=5:1), and thus 57 mg (cis:trans=4:1, 75%) of the title compound was obtained as a pale green powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: COC(=O)C(C)Oc1ncccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a mixture of 0.18 g of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}-pyridine, 0.19 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, and 2.0 ml of N,N-dimethylformamide was added 90 mg of potassium carbonate, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine as a mixture of diastereoisomers.