Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41](O)=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 18-[2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (12, 54 mg, 0.083 mmol) and carbonyldiimidazole (20 mg, 0.125 mmol, 1.5 eq) in dry THF (4 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (15 mg, 0.125 mmol) and DBU (19 mg, 0.125 mmol) were added. This solution was heated at 50° C. for 16 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography (gradient of EtOAc (0 to 50%) in DCM) afforded 45 mg (72%) of the title product which was recrystallized from water to give 12 mg of the desired product as a slightly yellow powder. m/z=751 (M+H)+. 1H NMR (CDCl3): 0.8-1.9 (m, 21H), 2.17 (m, 1H), 2.28-2.56 (m, 4H), 2.65 (m, 1H), 2.86, (m, 1H), 3.55 (m, 1H), 3.87 (m, 4H), 4.10 (m, 1H), 4.57 (m, 1H), 4.94 (t, J=9.5 Hz, 1H), 5.43 (m, 2H), 5.64 (m, 1H), 6.92 (broad s, 1H), 6.98 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.28 (m, 2H), 7.37 (s, 1H), 7.80 (d, J=9.0 Hz, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:15][C:16]([O:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[CH:19][CH:20]=1)([O-:9])=[O:8]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 19.3 g of p-nitrocinnamic acid suspended in 300 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, upon which p-nitrocinnamoyl chloride precipitated. The precipitates thus obtained were dissolved in 300 ml of ethyl acetate, and 9.4 g of phenol was added to the resulting solution, after which 12 g of triethylamine was slowly added thereto at room temperature with stirring. After reaction at room temperature for 1 hour, the reaction mixture was washed with 10% HCl, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to obtain phenyl p-nitrocinnamate. Yield: 25.5 g (95%); melting point: 151°-152° C.; IR (cm-1): 1720, 1529, 1345.
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([NH2:14])[CH3:13].CCN(C(C)C)C(C)C.C([N:32]=[C:33]=[S:34])(=O)C1C=CC=CC=1>C(Cl)Cl>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([NH:14][C:33]([NH2:32])=[S:34])[CH3:13]
Reactant: CC(N)c1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(N)=S)c1nc2ccccc2[nH]1
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
To a suspension of 1-(1H-Benzoimidazol-2-yl)-ethylamine dihydrochloride (0.50 g, 2.1 mmol) in CH2Cl2 (10 mL) was added DIPEA (0.74 mL, 4.3 mmol). After 5 minutes benzoyl isothiocyanate (0.32 mL, 2.4 mmol) was added and the reaction mixture was stirred for 2.5 h, followed by evaporation in vacuo. Ammonia (7M in MeOH, 20 mL) was then added and the reaction was stirred another 2.5 h. The excess ammonia was removed in vacuo and CH2Cl2 (10 mL) was added, the solid was collected by filtration giving the title compound (0.33 g, 70%). MS (ESI) m/z 221 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(C)(C)C.[Na+].C(OCC)(=O)C>C(COC)OC>[CH2:14]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: Brc1ccccc1C1CC1C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc(CNc2ccccc2C2CC2C2CC2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
3.7 g of 2-(2-bromophenyl)bicyclopropyl (15.6 mmol, trans/cis ratio of about 3:1), 2.0 g of benzylamine (18.7 mmol), 2.1 g of sodium tert-butanolate (21.8 mmol), 3.5 mg of Pd(II) acetate (0.016 mmol) and 8.6 mg of R(−)-di-tert-butyl-[1-[(S)-2-(dicyclohexylphosphanyl)-ferrocenyl]ethyl]phosphine (0.016 mmol) are dissolved in 30 ml of dimethoxyethane. The reaction mixture is heated to 70° C. and stirred for 24 hours. After cooling, ethyl acetate is added. The organic phase is washed with water. The solvent is removed using a water jet vacuum and the residue is dried. The product is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 1:15). 3.47 g of benzyl(2-bicyclopropyl-2-yl-phenyl)amine (84% of theory) are obtained in the form of a brown oil (trans/cis ratio of about 3:1).
Reaction SMILES: [CH:1]1[C:22]2[C:5](=[CH:6][C:7]3[C:8](=[O:24])[C:9]4[C:18]([C:19](=[O:23])[C:20]=3[CH:21]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=4)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[OH:23][C@H:19]1[C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:8]([OH:24])[C:7]2[CH:6]=[C:5]3[C:22]([CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:21][C:20]1=2
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1c2cc3ccccc3cc2[C@H](O)c2cc3ccccc3cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a suspension of 6,13-pentacenequinone (1.0 g, 3.24 mmol) in dry MeOH (40 mL) at 0° C. under an argon atmosphere was slowly added NaBH4 (1.22 g, 32.46 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and at RT for 1 h, and then quenched with H2O at 0° C. The resulting mixture was filtered and washed with H2O. The resulting solid was taken up in CHCl3, then filtered and washed with CHCl3, and dried in vacuo to give product as an off-white solid (0.92 g, 91%): mp 235° C. 1H NMR (500 MHz, DMSO-d6): δ 8.12 (s, 4H), 7.95 (m, 4H), 7.48 (m, 4H), 6.63 (s, 2H), 5.81 (s, 2H). 13C NMR (125.68 MHz, DMSO-d6): δ 138.19, 131.67, 127.47, 125.44, 120.91, 66.98. LDI-MS m/z: 312 [M+], 296 [M+-OH], 280 [M+-2(OH)].
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])[O-].[Cs+:17].[Cs+].C(O)(C)C.C(=O)=O>O>[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[Cs+:17]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cs+]
Solvent: CC(C)O
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Yield: 192 %

Procedure:
Ascorbic acid (5 g, 28.4 mmol) was dissolved in 20 ml of water, followed by slow addition of cesium carbonate (4.63 g, 14.2 mmol) in the temperature range of 0 to 5° C. 40 ml of isopropyl alcohol was slowly added to the reaction mixture when the generation of carbon dioxide completely stopped. After standing for several hours, the precipitate was filtered and washed with isopropyl alcohol, and dried to give 8.4 g of the cesium ascorbate as a white solid (yield 95%).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[Br:17][C:18]1[CH:19]=[C:20]([C:26]2[N:30]=[C:29]([C:31](OCC)=[O:32])[O:28][N:27]=2)[CH:21]=[C:22]([Br:25])[C:23]=1[OH:24].O>CCCCCC.C1(C)C=CC=CC=1>[Br:25][C:22]1[CH:21]=[C:20]([C:26]2[N:30]=[C:29]([C:31]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([O:7][C:6]([F:15])([F:16])[F:5])[CH:9]=3)=[O:32])[O:28][N:27]=2)[CH:19]=[C:18]([Br:17])[C:23]=1[OH:24]
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
Trimethylaluminum (0.075 mL of a 2 M solution in hexane, 0.15 mmol) was added to a stirred solution of 3-(trifluoromethoxy)aniline (26 mg, 0.15 mmol) in dry toluene (1 mL) under nitrogen. After stirring at room temperature for 1 hour, ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (58 mg, 0.15 mmol) was added in one portion and the mixture was stirred at room temperature for three days. Water (1 mL) was added and the mixture was extracted with ethyl acetate (3 mL). The organic phase was evaporated in vacuo to give a colourless oil which was purified by preparative HPLC to give the title compound (23 mg, 31%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 7.22 (1H, d), 7.69 (1H, t), 7.91 (1H, d), 7.98 (1H, s), 10.96 (1H, s, br), 11.97 (1H, s). LCMS (10 cm_apci_formic) tR 4.37 min; m/z 520/522/524 [M−H]−.
Reaction SMILES: [ClH:1].CC(CC(O)=O)=O.C(OC(=O)[NH:15][CH2:16][CH2:17][N:18]1[CH2:25][CH:24]2[O:26][CH:20]([CH2:21][N:22]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=3)[CH2:23]2)[CH2:19]1)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[NH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH:20]2[O:26][CH:24]([CH2:23][N:22]([CH2:27][CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=3)[CH2:21]2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Agent: CC(=O)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCN2CC3CN(CCN)CC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Hydrochloric acid (140 mmol, 35 mL of a 4 M solution in dioxane) was added to an ice-cooled slurry of the diacetate salt of (2-{7-[2-(4-cyanophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)carbamic acid tert-butyl ester (10.75 g, 20 mmol; see step (i) above) in dioxane (50 mL). The reaction mixture was stirred at RT overnight. Another 65 mL (260 mmol) of 4 M HCl solution was added, after which the reaction mixture was stirred for three hours and then evaporated. The residue was dissolved in water and washed with diethyl ether. Freeze-drying of the aqueous phase gave 8.3 g (97%) the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)[CH:6]=1.CN1C2C(=CC=C(C(O)=O)C=2)C(CC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=C1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6]2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccccc12
Agent: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Product: O=C(O)Cc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccccc12

Procedure:
This compound was prepared from the methyl ester (Example 17, part i) by the method described in Example 16, part iii. The product was recrystallised from ethyl acetate, m.p. 163°-166° C.
Reaction SMILES: [O:1]=[C:2]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])/[CH:3]=[CH:4]\[C:5]([OH:7])=O.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl>[Cl-].[Zn+2].[Cl-].O.C(Cl)(Cl)Cl>[O:15]=[C:14]([OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:5](=[O:7])[CH:4]=[CH:3][C:2]1=[O:1]
Reactant: O=C(O)/C=C\C(=O)NCCCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O
Temperature: 0 °C
Yield: 58.1 %

Procedure:
(z)-4-oxo-5-aza-undec-2-endioic acid, (160 g; 0.698 moles), zinc chloride, 280 g (2.05 moles), and phenothiazine, 0.15 g were added to a two liter round bottom flask fitted with an overhead stirrer, condenser, thermocouple, addition funnel, an inert gas inlet, and heating mantle. Chloroform (CHCl3), 320 mL was added to the 2 liter reaction flask, and stirring of the mixture was started. Triethylamine (480 mL; 348 g, 3.44 moles (TEA)) was added over one hour. Chlorotrimethyl silane (600 mL; 510 g, 4.69 moles) was then added over two hours. The reaction was brought to reflux and was refluxed overnight (˜16 hours). The reaction was cooled and added to a mixture of CHCl3 (500 mL), water (1.0 liters), ice (300 g), and 12 N hydrochloric acid (240 mL) in a 20 liter container over 15 minutes. After 15 minutes of stirring, the aqueous layer was tested to make sure the pH was less than 5. The organic layer was separated, and the aqueous layer was extracted three times with CHCl3 (700 mL) each extraction. The organic layers were combined and evaporated on a rotary evaporator. The residue was then placed in a 20 liter container. A solution of sodium bicarbonate (192 g) in water (2.4 liters) was added to the residue. The bicarbonate solution was stirred until the solids were dissolved. The bicarbonate solution was treated with a solution of hydrochloric acid, (26 liters of 1.1 N) over 5 minutes to a pH of below 2. The acidified mixture was then extracted with two portions of CHCl3, (1.2 liters and 0.8 liters) each extraction. The combined extracts were dried over sodium sulfate and evaporated. The residue was recrystallized from toluene and hexane. The crystalline product was then isolated by filtration and dried which produced 85.6 g of white N-(6-oxo-6-hydroxyhexyl)maleimide (Mal-EACA; Compound 2). Analysis on an NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3, 400 MHz) δ6.72 (s, 2H; maleimide protons), 3.52 (t, 2H, J=7.2 Hz; methylene next to maleimide), 2.35 (t, 2H, J=7.4; methylene next to carbonyl), 1.69-1.57 (m, 4H; methylenes adjacent to central methylene), and 1.39-1.30 (m, 2H; the central methylene). The product had a DSC (differential scanning calorimator) melting point peak at 89.9° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13]C=1)([CH3:3])[CH3:2].ClC1C=CC([N+]([O-])=O)=C[N:20]=1>>[CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[N:20]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)([CH3:2])[CH3:3]
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cn1

Procedure:
This compound is prepared according to the same procedure as described for Intermediate 7 using 2-chloro-5-nitropyridine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[NH4+]>ClCCl>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1Cc1ccc2ccccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN2CCNC(Cc3ccc4ccccc4c3)C2)cc1

Procedure:
To a solution of 4-benzyl-2-(naphthalen-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (0.75 g) in dichloromethane (3 mL) was added dropwise trifluoroacetic acid (3 mL). After 75 min at room temperature the mixture was poured onto ice and made basic by the addition of ammonium hydroxide (25% solution). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to afford 1-benzyl-3-(naphthalen-2-ylmethyl)piperazine as an oil; 053 g (93%) MH+ 317, Rf 0.61 (CH2Cl2/MeOH/NH4OH 93/7/0.5), which was used as such.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH:25]=O)=[CH:18][N:19]2[CH3:24].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:25][NH:6][CH3:5])=[CH:18][N:19]2[CH3:24]
Reactant: Cn1cc(C=O)c2c(Cl)cccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cccc(Cl)c12
Yield: 78 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 4-chloro-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.75 g, 78%) was obtained as a yellow solid: MS (ES) m/e 209.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:14])=[O:4]>C1COCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([CH3:14])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1C
Temperature: 25 °C

Procedure:
410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL of THF before a solution of 2.6 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction was re-cooled to 0° C. and another 2.6 mL of BH3-THF was added dropwise before the ice bath was removed. Upon completion, the reaction was re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbenzoate. 220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-methylbenzoate. 255 mg of methyl 4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45° C. for 1 hour via Procedure M to give 2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=O)[CH:5]=[C:6]([CH3:27])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:11][N:10]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][O:55][C:56]3[CH:63]=[CH:62][C:59]([C:60]#[N:61])=[CH:58][CH:57]=3)=[CH:49][CH:48]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.CCOC(OC(OCC)=O)=O.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([N:43]2[CH2:42][CH2:41][N:40]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]([CH2:53][CH2:54][O:55][C:56]4[CH:57]=[CH:58][C:59]([C:60]#[N:61])=[CH:62][CH:63]=4)=[CH:51][CH:52]=3)[CH2:45][CH2:44]2)=[O:32])[CH:5]=[C:6]([CH3:27])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)=[CH:11][N:10]=1
Reactant: Cc1cc(/C=C/C(=O)O)cc(Cl)c1Oc1ccc(OCc2ccc(C(F)(F)F)cc2)cn1
Reactant: N#Cc1ccc(OCCc2ccc(CN3CCNCC3)cc2)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCOc4ccc(C#N)cc4)cc3)CC2)cc(Cl)c1Oc1ccc(OCc2ccc(C(F)(F)F)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{3-chloro-5-methyl-4-[(5-{[4-(trifluoromethyl)benzyl]-oxy}pyridin-2-yl)oxy]phenyl}prop-2-enoic acid (139 mg) and 4-{2-[4-(piperazin-1-ylmethyl)-phenyl]ethoxy}benzonitrile trifluoroacetate (131 mg) in DMF (6 mL) was added DEPC (0.073 mL) and Et3N (0.165 mL) at 0° C. After stirring at 0° C. for 1 hour, to the reaction mixture was added H2O, and extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to give 4-{2-[4-({4-[(E)-3-{3-chloro-5-methyl-4-[(5-{[4-(trifluoromethyl)benzyl]oxy}pyridin-2-yl)oxy]phenyl}prop-2-enoyl]piperazin-1-yl}methyl)phenyl]ethoxy}benzonitrile as a pale yellow amorphous (195 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:33]2([CH3:34])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:28])[CH2:18][CH2:19][CH2:20][C:21]([O:24][C:25](=[O:27])[CH3:26])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[CH2:6]1)(=[O:3])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O.CC1C=C(C)N=C(C)C=1>CCCCCC.C1(C)C(C)=CC=CC=1.C(OC(=O)C)C>[C:1]([O:4][C@@H:5]1[C@@:33]2([CH3:34])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:28])[CH2:18][CH2:19][CH2:20][C:21]([O:24][C:25](=[O:27])[CH3:26])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of 1α,3β,25-triacetoxycholest-5-ene (544 mg, 1 m mole) in dry hexane (10 m), 1,3-dibromo-5,5-dimethylhydantoin (172 mg, 0.6 m moles) was added dropwise under stirring and heating at oil bath temperature of 95° C., and the mixture was continued to react under the irradiation of infrared rays for 15 minutes. The reaction mixture was cooled, and the resulting precipitate was removed by filtration, the filtrate was concentrated at reduced pressure at 40° C. to afford a residual product. Xylene was added to this substance to form a solution. The resulting solution was added dropwise to a solution held at 170° C. of s-collidine (2.5 ml) in dry xylene (3 ml), and the reaction was carried out for additional 20 minutes. After the reaction, the resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure at 40° C. to give residual product. The product was dissolved in ethylacetate (20 ml). The ethylacetate solution was washed with 1 N hydrochloric acid (3×10 ml), saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 473 mg of residual product.