Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:30]2[O:31][C:32]([C:38]([F:41])([F:40])[F:39])=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35]([C:33]3[N:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:31][C:32]=3[C:38]([F:40])([F:41])[F:39])=[O:36])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1

Procedure:
To a solution of 4-fluoronitrobenzene (1.41 g, 10 mmol) in THF (50 mL) was added N-Boc-4-hydroxypiperidine (2.01 g, 10 mmol) and sodium hydride (60% in mineral oil, 583 mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.51 g, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+1) 532.20, obsd 532.1
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][NH:3]1.FC(F)(F)C(O)=O.ClC1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[S:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=2)[CH:30]=1.C(N(CC)CC)C>>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]4[S:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=4)[CH:30]=3)[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCCNC2=O)CC1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc(N3CCN(C4CCCNC4=O)CC3)ncn2)s1
Temperature: 150 °C

Procedure:
51-2 (0.15 g, 0.53 mmol) was first treated with neat trifluoroacetic acid for 30 minutes at room temperature. The trifluoroacetic acid was then evaporated off and the residue was dissolved in n-butanol (3 mL). To this was added 35-1 (0.13 g, 0.53 mmol) and triethylamine (0.27 g, 2.65 mmol). This was heated at 150° C. for 18 hours and then the solid was filtered off, washed with n-butanol and then ethyl ether to afford 51-3. Hi-Res MS: calc: 385.1554 found: 385.1551. 1H-NMR (DMSO-d6): 12.02 (s, 1H); 8.41 (s, 1H); 8.25 (s, 1H); 7.44 (s, 1H); 6.20 (s, 1H); 3.51 (br s, 4H); 3.13 (m, 1H); 3.05 (m, 2H); 2.93 (m, 2H); 2.63 (m, 2H); 1.62–1.83 (complex, 4H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound : MS ES+368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1(C)C=CC=CC=1.C(O)C.[OH-].[Na+].O>[OH:8][C:7]1[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccnc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cccnc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A mixture of 2-bromo-3-hydroxypyridine (2.20 g, 12.6 mmol), phenylboronic acid (2.00 g, 16.3 mmol) and palladium (tetrakis)triphenylphosphine (250 mg) in toluene (30 mL), ethanol (15 mL) and 5% aqueous sodium hydroxide (15 mL) was degassed with a stream of nitrogen and stirred vigorously at 100° C. overnight. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL), and the organic layer was dried over sodium sulfate and concentrated, affording a yellow solid. This material was suspended in water (100 mL), a few mL of 1N HCl was added, and the resulting solution was extracted with ethyl acetate. The aqeuous layer was neutralized with saturated aqueous sodium bicarbonate, and again was extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated to an oily solid, which was triturated with 2:1 hexane/ethylacetate, affording 0.98 g of 3-hydroxy-2-phenylpyridine.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17](S(C)(=O)=O)[N:16]=1.O>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[N:16]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
25 g (230 mmol) Methyl thioglycolate was dissolved in 250 ml dimethylformamide and treated with 16.3 g (115 mmol) potassium carbonate. After 20 minutes stirring at room temperature, 50 g (2.3 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added and the mixture heated for 3 hours at 90° C. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulphate. The solvent was distilled and the resulting crude product was recrystallised from diisopropyl ether.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=[O:5])=[O:4]>O1CCOCC1.C(Cl)Cl>[Cl-:1].[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH2+:9][CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CC[NH2+]CC1
Product: [Cl-]
Reaction time: 20 h
Yield: 97 %

Procedure:
A 4M hydrogen chloride solution in 1,4-dioxane (1.2 L) was added slowly to a cold solution of tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate 7 (105 g) in methylene chloride (1.1 L) while maintaining the internal temperature below 20° C. The solution was stirred for 20 hours and 1H NMR indicated that the reaction was complete. The resulting slurry was filtered and rinsed with methylene chloride (300 ml). The cake was dried in a vacuum oven at 50° C. for 20 hours to afford 4-(methylsulfonyl)piperazin-1-ium chloride 8 as a white solid (78.4 g, 97% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ 3.00 (s, 3H), 3.17 (m, 4H), 3.38 (m, 4H), 9.45 (br s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[Si](C)(C)C.[Br:41]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:8][C:9](=[O:25])[CH:10]([Br:41])[CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)n1ccc(CCCC(=O)OCc2ccccc2)n1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(CCC(Br)C(=O)OCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 27.5 g (80.0 mmol) of tert-butyl 3-[4-(benzyloxy)-4-oxobutyl]-1H-pyrazole-1-carboxylate from step D above in 250 mL of anhydrous THF at −78° C. under an atmosphere of nitrogen was added 88 mL (88 mmol) of a 1.0 M solution of sodium bis(trimethylsilyl)amide in anhydrous THF. The resulting dark yellow solution was stirred for 1 h at −78° C. and then 12 mL (96 mmol) of chlorotrimethylsilane was added dropwise over 5 min. The resulting mixture was stirred for 25 min during which time the reaction became a light yellow color. Next, 16 g (88 mmol) of solid N-bromosuccinimide was added in one portion and the resulting mixture was stirred for 3 h at −78° C. followed by gradual warming to 0° C. over 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution and the aqueous phase extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a yellow gum. The crude product appears to be a 1:1 mixture of starting material and desired product by NMR and was used without further purification in the next step. LC-MS: m/z (ES) 424 (MH)+.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.BrCCCl.[CH:18]1[N:19]=[CH:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]=12>C1COCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:23]2([OH:27])[CH2:24][CH2:25][CH2:26][N:21]3[CH:20]=[N:19][CH:18]=[C:22]23)=[CH:6][CH:5]=1
Reactant: O=C1CCCn2cncc21
Reactant: COc1ccc(CCCBr)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCBr
Product: COc1ccc(CCCC2(O)CCCn3cncc32)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A three-necked flask with dropping funnel and reflux condenser is charged with 285.000 mmol of magnesium turnings in 50 ml of THF. With stirring at an oil bath temperature of 70° C. a solution of 37.100 mmol of 3-(4-methoxyphenyl)bromopropane [57293-19-3] and 28.500 mmol 1-bromo-2-chloroethane in 40 ml of THF is added dropwise over 45 minutes. The mixture is subsequently stirred at 70° C. for 2 hours and then cooled to room temperature and the supernatant solution is transferred using a transfer cannula into a second three-necked flask, fitted with dropping funnel. The Grignard solution thus obtained is admixed dropwise, with ice-bath cooling, with 28.500 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in solution in 50 ml of THF over 10 minutes. When addition is complete the reaction mixture is stirred at room temperature for 1 hour. It is quenched with 150 ml of 0.5M aqueous HCl and extracted with dichloromethane (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as an amber oil. Rf=0.08 (dichloromethane-ethanol=98:2); Rt=5.50.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:16]1([C:22]([C:24]([F:27])([F:26])[F:25])=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2([C:24]([F:25])([F:26])[F:27])[C:5]3[CH:6]=[C:1]([CH3:15])[CH:2]=[CH:3][C:4]=3[O:7][C:8]3[C:13]2=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Product: Cc1ccc2c(c1)C(c1ccccc1)(C(F)(F)F)c1cc(C)ccc1O2

Procedure:
A mixture of 114 g (0.54 mole) p-tolyl ether (X), 100 g (0.54 mole) trifluoromethyl phenyl ketone, and 160 g (8 moles) HF was heated in an autoclave for 8 hrs at 130°. After venting excess HF, the reaction mixture was quenched in 2 L ice water, containing 500 ml 50% NaOH. The product was extracted with methylene chloride, the extracts were filtered through a layer of alumina, stripped and distilled in vacuo. There was obtained 140 g (73%) of distillate boiling at 186°-210°/2 Torr. The solid was recrystallized from methanol or isopropyl alcohol. M.p. 150°-151°. NMR: d 7.40, m 7.30, s 7.07, s(b) 6.64, s 2.16 ppm in 2:3:4:2:6 ratio. Analysis: Calc. for C22H17F3O: C 74.6; H 4.80; F 16.1; Found: C 74.7; H 4.90; F 15.9%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.CC(O)=O.CC(O)=O.[Pd]>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:11]1[N:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: Fc1cccc(F)c1-c1ncc(-c2ccc(Br)cc2)cn1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1ncc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cn1

Procedure:
0.70 g of 5-(4-bromophenyl)-2-(2,6-difluorophenyl)-pyrimidine, 0.53 g of 4-trifluoromethoxyphenyl-boric acid and 0.07 g of palladium-II-acetate are heated under reflux for 1½ hours, under nitrogen, in a mixture of 20 ml of dimethoxyethane and 20 ml of saturated, aqueous potassium carbonate solution. The reaction mixture is then cooled, diluted with water and the crystalline precipitate filtered. After dissolving the precipitate in ethyl acetate, drying with magnesium sulfate, filtering and concentrating, the title compound is obtained in the form of light yellow crystals with a melting point of 215-216° C.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>C(O)(C)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:21]([F:26])[CH:20]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1ccc2c(Nc3ccc(Cl)cc3F)ncnc2c1
Yield: 83.9 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride (624 mg, 2.27 mmol) and 4-chloro-2-fluoroaniline (305 μl, 2.6 mmol) in isopropanol (20 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution, then with water, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether to give 4-(4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)quinazoline (662 mg, 84%) as a white solid.
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[C:9]([O:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])(=[O:11])[CH3:10].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH3:2][O:17][C:16](=[O:18])[C@H:14]([CH2:13][O:12][C:9](=[O:11])[CH3:10])[NH2:15]
Reactant: CC(=O)OC[C@H](N)C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)COC(C)=O
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of O-acetylserine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give O-acetylserine methyl ester isocyanate.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C1COCC1>[O:22]=[C:20]([CH3:21])[CH2:19][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CC(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CSc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Mercapto-benzoic acid (5.0 g, 32.3 mmol) and triethylamine (11.3 mL, 81.1 mmol) were dissolved in THF at 0° C. Chloroacetone (2.7 mL, 33.9 mmol) was then added and the reaction was allowed to slowly warm to room temperature as it stirred overnight. Standard aqueous workup afforded the title compound which was brought forward to the next step without further purification.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NCCc1ccc(O)cc1
Product: COc1ccc(C(=O)NCCc2ccc(O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.03 g of the target compound is obtained as white solid in substantially the same manner as in Example 11, except for using 3-adamantan-1-yl-4-methoxybenzoic acid instead of 3-adamantan-1-yl-4-hydroxybenzoic acid and using tyramine instead of 3,4-dihydroxybenzylamine.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[NH:4].[Cl:15][C:16]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][C:17]=1[C:18](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:15][C:16]1[CH:25]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[CH:23]=[CH:22][C:17]=1[C:18]1[O:1][N:2]=[C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[CH:7]=[CH:8][N:9]=[CH:10]3)[N:4]=1
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: COC(=O)c1ccc(OC(C)C)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)c(Cl)c1
Yield: 13.7 %

Procedure:
N-hydroxy-5-isoquinolinecarboximidamide (D1, 30 mg, 0.160 mmol) was stirred in DMF (0.7 ml) with methyl 2-chloro-4-[(1-methylethyl)oxy]benzoate (D32; 40.3 mg, 0.176 mmol) and sodium hydride (60%; 4.61 mg, 0.115 mmol) in a Biotage Initiator microwave at 100° C. for 30 mins. The cooled mixture was concentrated under vacuum and the residue was purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound as a pale yellow solid (8 mg).
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].CN(C=O)C.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:18][C:17]1[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([O:20][CH2:4][C:3]([CH3:5])=[CH2:2])[C:12]=1[CH3:11]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)COc1cc(C)cc(C)c1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
3-bromo-2-methylpropene (29.8 g, 221 mmol) was added to a mixture of DMF (130 mL) containing 2,3,5-trimethylphenol (25.0 g, 184 mmol) and potassium carbonate (50.9 g, 368 mmol), and the resulting mixture was stirred at 80° C. for 15 hours. After cooled to room temperature, the reaction solution was distributed using ethyl acetate and water. The organic layer was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 50:1 to 9:1) to give 33.6 g of the title compound (yield: 96%) as an oily product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1ccc2cccnc2c1)c1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2cccnc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 21.5 h

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-quinolin-7-ylmethanol (600 mg, 2.21 mmol), phthalimide (356 mg, 2.42 mmol), and PS-PPh3 (loading 2.12 mmol/g; 1.56 g, 3.31 mmol) in dry THF (20 mL), cooled by ice/water, was added DIAD (480 μL, 493 mg, 2.44 mmol), then the cooling bath was removed and the flask was vortexed at ambient temperature for 21.5 h. More PS-PPh3 (520 mg, 1.10 mmol) and DIAD (160 μL, 164 mg, 0.81 mmol) were added, and vortexing was continued for 6.5 h. The resin was filtered and washed with THF and CH2Cl2. The crude material was chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 3:1 (1-14)→2:1 (15-29)→1:1 (30-65)→1:2 (66-80)], yielding the title compound as pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, 1H), 7.41 (dd, J=4.4, 8.0 Hz, 1H), 7.54 (dd, J=2.0, 8.4 Hz, 1H), 7.72-7.78 (m, 2H), 7.81-7.89 (m, 3H), 8.01 (d, J=0.8 Hz, 1H), 8.16 (dd, J=0.8, 8.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 401.0/402.9 (100/38) [MH+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: NCCCCO
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCCCO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and 4-amino-1-butanol (3.4 ml, 37 mmol) were dissolved in DMF (45 ml). 1-hydroxybenzotriazole (5.0 g, 37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol), and diisopropylethylamine (10.7 ml, 61.7 mmol) were added sequentially to the solution and allowed to stir at room temperature overnight. After removing excess solvent in vacuo, the residue was taken up in water and the product was extracted into dichloromethane. The organics were combined, washed with brine, dried over Na2SO4, and solvent removed in vacuo to give a solid which was purified by column chromatography (100% ethyl acetate) to give 3.5 g (50% yield) of a white solid. 1H NMR (DMSO-d6): δ1.35-1.62 (m, CH2, CH2), 3.29 (q, CH2), 3.41 (q, CH2), 4.3 (t, NH), 7.78 (d, 1 Ar H), 7.63 (d, 1 Ar H), 7.51 (s, 1 Ar H), 7.46 (t, 1 Ar H), 7.35 (t, 1 Ar H), 8.71 (t, NH) Electrospray Mass Spec: m/z 234.2 (M+H)+.