Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:24](O)=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1>[C:1]([NH:8][C@H:9]([CH2:24][OH:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1
Yield: 81.4 %

Procedure:
A well, stirred cold solution (0° C.) of Nα-Boc-Nδ-Cbz-ornithine (5 g, 13.6 mmol), diisopropylethylamine (5.9 ml, 34 mmol), and tetrahydrofuran (60 ml) was treated with ethyl chloroformate (3.25 ml, 34 mmol) at 0° C. Sodium borohydride (2.58 g, 68 mmol) was added, followed by the slow addition of 1:1-tetrahydrofuran/water (10 ml) 30 minutes later. The reaction mixture was acidified with 6N hydrochloric acid and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and purified by chromatography to give Nα-Boc-Nδ-Cbz-ornithinol (3.9 g): 1H NMR (400 MHz, CDCl3) δ1.2-1.4 (m, 13H), 3.0 (t, J=6.4 Hz, 2H), 3.4 (s, 2H), 3.8 (s, 1H), 4.95 (s, 2H), and 7.1-7.2 (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:16]3[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH:28]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.O>[O:29]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:16]3[C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH:28]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:6]=1)[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Yield: 68.1 %

Procedure:
A mixture of alpha-oxo-4-[[2-(9-phenanthrenyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.685 g) in hot tetrahydrofuran (100 mL) was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the aqueous solution was acidified with excess hydrochloric acid and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.45 g of alpha-oxo-4-[[2-(9-phenanthrenyloxy) ethyl]oxy]benzeneacetic acid as a colorless solid, mp 179°-180° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([C:33](=[O:32])[CH2:34][OH:35])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)CO)C1
Temperature: 4 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.25 g; prepared as described in Example 29) was dissolved in a mixture of methylene chloride (10 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.069 ml) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in 7M methanolic ammonia (10 ml) and the resulting solution stirred overnight. The solvent was evaporated and the residue purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) 98/2 to 92/8 The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a pale yellow solid (0.161 g, 61%); 3H NMR Spectrum: (DMSO-d6 @ 393K, 500 MHz) 2.10-2.40 (m, 2H), 3.50-3.70 (m, 3H), 3.70-3.85 (m, 1H), 3.95 (s, 3H), 4.05 (s, 2H), 5.15 (s, 1H), 7.15-730 (m, 2H), 7.30-7.45 (m, 1H), 7.50-7.70 (m, 1H), 7.85 (s, 1H), 8.40 (s, 1H), 9.20 (bs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: O([Si](C)(C)C)[K].I[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:17](/[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Ic1cccc2ccccc12
Agent: [Pd]
Agent: C[Si](C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCC/C=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Following General Procedure II, a mixture of KOSiMe3 (570 mg, 4.0 mmol, 2.0 equiv), (Z)-21 (379 mg, 2.2 mmol, 1.1 equiv), 1-iodonaphthalene (292 μL, 2.0 mmol) and Pd(dba)2 258 mg, 0.1 mmol, 0.05 equiv) was stirred at room temperature for 9 h, and then was filtered through SiO2. Purification by column chromatography (RP C18, MeOH/H2O, 9/1) and Kugelrohr distillation afforded 394 mg (88%) of (Z)-154a as colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.C(OCC)(=O)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:16]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccsc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(-c3ccsc3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of tert-butyl 9-(3-thienyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (140 mg, 0.422 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (105 mg, 92.9%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[OH-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CO.O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:19][CH2:18][CH:17]=[CH2:16])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: C=CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 70 °C
Reaction time: 27 h

Procedure:
41.5 g of 3-methyl-xanthine are added with stirring at 70° C. to a solution of 10.2 g of NaOH in 400 ml of methanol/water (1:1). After mixing with 35.1 g of 4-bromobut-1-ene the mixture is stirred under a nitrogen atmosphere for 27 hours at 70° C. The reaction mixture is then cooled to 20° C. and the precipitate formed is filtered off. By re-precipitation from alkaline solution (pH 13.5) and acidification with dilute sulphuric acid to pH 10, 29.6 g (89.7% of theory relative to reacted 3-methyl-xanthine) of the title compound of melting point 245° to 246° C. are obtained after drying.
Reaction SMILES: Cl.[NH2:2][OH:3].CC[O-].[Na+].[Na].[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=1[C:13]#[N:14]>C(O)C>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:11]([O:10][CH3:9])[C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: NO
Reactant: COc1cc(OC)c(C#N)c(OC)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)c(C(N)=NO)c(OC)c1

Procedure:
To a suspension of 13.8 g of hydroxylamine hydrochloride in 100 ml of ethanol is added, at a temperature in the region of 15° C., a solution of NaOC2H5 prepared by dissolving 4.3 g of sodium in 100 ml of ethanol. 12 g of 2,4,6-trimethoxybenzonitrile are introduced into the medium, followed by heating at reflux for 41 h before evaporating to dryness. The crystals are washed with water and with dichloromethane.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([C:26]([F:30])=[C:27]([F:29])[CH:28]=1)[CH:24]=[O:25])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([CH:24]([C:2]2[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)[OH:25])[C:26]([F:30])=[C:27]([F:29])[CH:28]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C=O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (753.6 mg, 3.307 mmol, Matrix Chemicals) in tetrahydrofuran (20 mL) cooled to −30° C. was added dropwise isopropylmagnesium chloride. The temperature was maintained below −25° C. throughout the addition. At the end of addition, the reaction mixture was stirred at −30° C. for 20 minutes and a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-benzaldehyde (1 g, 3.307 mmol, Example 266) in tetrahydrofuran was added dropwise. The temperature was maintained below −25° C. throughout the addition. The reaction mixture was allowed to warm up to 0° C. after the addition was completed. After being stirred at 0° C. for 45 minutes, saturated solution of ammonium chloride (−3 mL) was added. The mixture was taken up in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 5–10% ethyl acetate in hexanes) yielded [3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-(2,4-dichloro-pyrimidin-5-yl)-methanol as white solids (965 mg, 65%). LR-MS (M+) 451.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2Br)[O:6][CH2:5][CH2:4][O:3]1.C([Li])CCC.[CH3:19][C:20]1[C:21](=[O:28])[CH:22]([CH3:27])[CH:23]([CH3:26])[C:24]=1[CH3:25].C1(C)C=CC=CC=1>O1CCCC1.CCCCCC.O>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:21]2([OH:28])[CH:22]([CH3:27])[CH:23]([CH3:26])[C:24]([CH3:25])=[C:20]2[CH3:19])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC1(c2ccccc2Br)OCCO1
Reactant: CC1=C(C)C(C)C(C)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC1=C(C)C(O)(c2ccccc2C2(C)OCCO2)C(C)C1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(2-methyl-1,3-dioxolan-2-yl)-bromobenzene (1.22 g, 5.0 mmol) in tetrahydrofuran (7.3 g) was cooled to −10° C. and a solution of n-butyllithium in n-hexane (1.56 M, 3.4 mL) was added dropwise thereto. After keeping the temperature for 1 hr, a solution of 2,3,4,5-tetramethylcyclopentenone (0.73 g, 5.3 mmol) in tetrahydrofuran (4.9 g) was added dropwise to the mixture. After raising the temperature to 25° C., the mixture was stirred for 3 hrs. After quenching the reaction by addition of toluene and water, the aqueous layer was removed. The obtained organic layer was washed with saturated brine and then dried over sodium sulfate, and the solvent was removed. After concentration, the residue was washed with cooled hexane to give 1-(2-methyl-1,3-dioxolan-2-yl)-2-(1-hydroxy-2,3,4,5-tetramethyl-2-cyclopentenyl)benzene (0.53 g, yield 35.0%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][C:7]=1[CH:15]([NH:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](=[N:31]/[H])/[NH:29]O)=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19]C)=[O:17])(=[O:3])[NH2:2]>CO.C(O)(=O)C.[Ni]>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:15]([C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][C:1](=[O:3])[NH2:2])[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:26]=1)(=[NH:29])[NH2:31]
Reactant: [H]/N=C(\NO)c1ccc(NC(C(=O)OCC)c2cc(OCC)ccc2OCC(N)=O)cc1
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(OCC(N)=O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)c1
Yield: 93.4 %

Procedure:
305 mg of ethyl (Z)-(RS)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate were treated in 8 ml of methanol-acetic acid (1:1) with Raney-nickel and stirred under hydrogen. The reaction mixture was filtered, evaporated in a vacuum and, for purification, the residue was triturated in acetonitrile. There were obtained 265 mg of methyl (RS)-(4-carbamimidoyl-phenylamino)-(2-carbamoylmethoxy-5-ethoxy-phenyl)-acetate; m.p. 200° C. (dec.), MS: 401 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (0.5 g, 1.97 mmol) in DMF (10 mL) was added NaH (80 mg, 1.97 mmol) and the suspension was stirred for 20 minutes under nitrogen. This was followed by the addition of (3-bromopropoxy)(tert-butyl)dimethylsilane (457 μL, 1.97 mmol) and the reaction mixture was heated to 100° C. under nitrogen overnight. The solvent was removed to yield crude 4-(5-(4-fluorobenzyl)-1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-pyrazol-3-yl)pyridine that was taken into THF (10 mL) at 0° C. and TBAF (1 M in THF, 1.97 mL, 1.97 mmol) was added. The mixture was stirred at 0° C. for 1 hour followed by stirring at room temperature for 1 hour. The solvent was removed and the residue was diluted with EtOAc and washed with H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (2-5% MeOH/CH2Cl2) then again using 3% MeOH/EtOAc followed by trituration with Et2O to yield the title compound as a white solid (0.33 g, 54%). 1H NMR (400 MHz, DICHLOROMETHANE-D2) δ ppm 8.55 (d, 2 H), 7.60 (d, 2 H), 7.16-7.24 (m, 2 H), 7.04 (t, 2 H), 6.40 (s, 1 H), 4.18 (t, 2 H), 4.03 (s, 2 H), 3.57 (t, 2 H), 1.87-1.96 (m, 2 H); m/z (APCI+) for C18H18N3FO 312.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[O:11][C:12]=1[CH3:13].[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:21]=[CH:20][CH:19]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[O:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1cccc(CCl)c1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccco3)oc2C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.04 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.46 g, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29](=[O:39])[N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:6]=1[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64]([N:67]1[C:75]2[C:70](=[CH:71][C:72]([S:76]([NH2:79])(=[O:78])=[O:77])=[CH:73][CH:74]=2)[CH2:69][CH2:68]1)(=[O:66])[CH3:65].C(N(C(C)C)C(C)C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[C:64]([N:67]1[C:75]2[C:70](=[CH:71][C:72]([S:76]([NH:79][C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:5]4[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:29]([N:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])=[O:39])=[N:4]4)=[C:9]([C:17]([N:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20]4)=[O:18])[CH:10]=3)=[O:13])(=[O:77])=[O:78])=[CH:73][CH:74]=2)[CH2:69][CH2:68]1)(=[O:66])[CH3:65]
Reactant: CC(=O)N1CCc2cc(S(N)(=O)=O)ccc21
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4c(c3)CCN4C(C)=O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a solution of 4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (Intermediate 1F, 30 mg, 0.054 mmol) in DMF (2.0 mL) was added HATU (29 mg, 0.076 mmol), 1-acetylindoline-5-sulfonamide (20 mg, 0.082 mmol), DMAP (7 mg, 0.054 mmol) and i-Pr2EtN (0.029 mL, 0.163 mmol). The resulting reaction mixture was stirred at room temperature for 3 h and then diluted with EtOAc and 1N aq. HCl solution. The organic layer was washed with 1N aq. NaOH solution (2×) followed by 1N aq. HCl solution (1×). The combined aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a crude oil, which was purified using preparative HPLC to give the title compound (10 mg, 24%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.19-8.16 (m, 2H), 8.08-8.06 (m, 1H), 7.89-7.86 (m, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.22-7.10 (m, 3.5H), 6.94 (d, J=7.3 Hz, 0.5H), 4.75-4.50 (m, 2H), 4.22-4.18 (m, 2H), 3.90-3.40 (m, 4H), 3.15-2.65 (m, 4H), 2.33 (s, 2H), 2.28 (s, 1H), 2.25 (s, 3H), 1.52-1.00 (m, 10H), 0.95-0.88 (m, 3H), 0.79-0.75 (m, 2H), 0.71-0.67 (m, 1H); MS(ESI+) m/z 773.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:16]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCl)Nc1cccc2ncccc12
Reaction time: 8 h
Yield: 30 %

Procedure:
In 60 ml of methylene chloride was dissolved 4.5 g of 5-aminoquinoline, and 10.5 g of 3-chloropropionyl chloride and 9 g of triethylamine were then added thereto. After the liquid was allowed to stand at room temperature overnight, a 1N aqueous sodium hydroxide solution was added to the liquid, and the latter was then extracted with methylene chloride. The extract was washed twice with an aqueous sodium bicarbonate solution, was then dried, and was concentrated to obtain crystals. The latter were washed with methylene chloride, and filtered to obtain 2.2 g of 5-(3-chloropropionamido)quinoline in a crystalline state.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][SiH2:9][O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])(=[O:4])[CH:2]=[CH2:3].C([O:18][CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[OH:18][CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:1]([O:5][CH2:6][CH2:7][CH2:8][SiH2:9][O:10][Si:11]([CH3:14])([CH3:12])[CH3:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(=O)OC=Cc1ccccc1
Agent: C=CC(=O)OCCC[SiH2]O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: OC=Cc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
12.5 g (3-acryloxypropyl)trimethylsiloxy silane, 28 g acetoxystyrene and 2.01 g AIBN were dissolved in 122 g THF and charged into a 3-neck flask. The system was then purged with N2 for 30 mins before the temperature was raised to 65° C. The reaction was carried out overnight under N2. On the second day, 100 g methanol and 30 mL 30% ammonia hydroxide were added to the system and the temperature was kept at 60° C. The reaction was carried out overnight under N2. On the third day, the solution was precipitated in 2000 mL water and 20 mL acetic acid. The polymer was collected and dried in vacuum oven overnight at 40° C. The molecular weight was determined by GPC to be 6.5K.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH:33]1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)[CH:34]=1.[Na+].[Na+].[Na+].N(CC)(C(C)C)C(C)C.C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.[Cu]I.CCOC(C)=O>[C:33]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:26]([F:32])[CH:27]=1)#[CH:34]
Reactant: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Reactant: CC(C)(O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)cc(/C=N/OCC(C)(C)O)c(F)c2F)c(F)c1
Reaction time: 1 h
Yield: 574.9 %

Procedure:
(E)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-propoxyimino)-methyl]-benzamide (200 mg, 0.35 mmol), Pd(CH3CN)2Cl2 (4.5 mg, 0.0176 mmol), triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (25.0 mg, 0.037 mmol), N(iPr)2Et (48.0 mg, 0.37 mmol), trimethylsilyl acetylene (172 mg, 1.76 mmol), and CuI (3.4 mg, 0.0176 mmol) were stirred in MeOH at room temperature for 1 hour, and the solvent was evaporated. The resultant residue was added to THF/H2O containing tetrabutylammonium fluoride (0.35 mmol), and the mixture was stirred for 1 hour. EtOAc was added thereto, and the organic layer was washed with 0.4 N aqueous HCl, dried over Na2SO4, and evaporated. The resultant residue was purified by silica gel chromatography (CH2Cl2/MeOH as a developing solvent) to give a title compound (99 mg).