Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].[CH3:26][NH:27][CH:28]([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH:28]([N:27]([CH3:26])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: CNC(C)C
Agent: [N-]=C=O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), N-methylisopropylamine (0.58 ml), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[6-{2-[isopropyl(methyl)amino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.135 g); Mass Spectrum: M+H+ 396.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>C(O)(=O)C.O>[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: Cn1ccc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Sodium cyanoborohydride (63 mg, 1. 004 mmol) was added to an ice-cold solution of the N-methyl indole (110 mg, 0.335 mmol) in glacial acetic acid (6 mL). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, cooled in an ice bath, and diluted with H2O (10 mL). Ice-cold concentrated aq. ammonium hydroxide (30 mL) was added until the solution reached pH 12. After extraction (2×) with CH2Cl2, the organic layer was dried over MgSO4/Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, 10 g, 10% EtOAc/hexanes) gave the desired N-methyl indoline product (15 mg, 15%) as brown oil. The material is air-sensitive and requires storage under nitrogen: 1H NMR (500 MHz, CDCl3) δ7.28-7.25 (m, 1H), 7.01 (dd, J=10.4, 2.0 Hz, 1H), 6.95 (dd, J=8.2, 1.9 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.28 (d, J=8.1 Hz, 1H), 4.11 (t, J=5.9 Hz, 1H), 3.50 (dd, J=13, 2.0 Hz, 2H), 3.36-3.32 (m, 2H), 2.88 (dd, J=11.3, 5.2 Hz, 1H), 2.82 (t, J=8.2 Hz, 2H), 2.73 (s, 3H), 2.56 (dd, J=11.4, 7.0 Hz, 1H), 2.41 (s, 3H); IR (KBr) 3052, 2925, 2850, 2786, 1609, 1422, 1265, 739 cm−1; ESI MS m/z=331 [C19H20ClFN2+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16](I)[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].CC#N>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.CCOC(C)=O>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=c1ccn(Cc2ccccc2)c2oc(I)c(-c3ccccc3)c12
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: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1cccc(-c2oc3c(c2-c2ccccc2)c(=O)ccn3Cc2ccccc2)c1
Temperature: 85 °C

Procedure:
To a mixture of iodide 4f (2.94 g, 6.89 mmol, 1.0 equiv), 3-carboxyphenylboronic acid (1.26 g, 7.57 mmol, 1.1 equiv), tetrakis(triphenylphosphine)palladium (0.796 g, 0.689 mmol, 0.1 equiv), and sodium carbonate (2.92 g, 27.6 mmol, 4.0 equiv), was added MeCN (30 mL) and H2O (30 mL). The slurry was heated at 85° C. for 8 h. After cooling to rt, EtOAc (ca. 100 mL) and H2O (ca. 50 mL) were added. The aqueous layer was separated, filtered, and acidified with 1N HCl. The resulting white precipitate was filtered to provide acid 4k. MS (MH+) 422; Calculated 421.1 for C27H19NO4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38].[H-].[Na+].[CH2:41](Br)[C:42]#[CH:43].C1(C)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:41][C:42]#[CH:43]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-ol (150 mg, 22.89 mmol, 1.0 equiv.) was slowly added to a slurry of NaH (48 mg, 45.78 mol, 8 equiv.) in DMF (1.4 mL) in a flame dried flask pre-cooled to 0° C. 80% propargyl bromide in toluene (36 □L, 27.47 mmol, 1.2 equiv.), cooled to 0° C., was added slowly. The ice bath was removed and the reaction was allowed to stir at room temperature for an additional 2 hours. The reaction was then re-cooled to 0° C., 0.5 mL of ice cold water was added, and the reaction was concentrated under reduced pressure. The remaining residue was redissolved in dichloromethane, then partially purified via silica gel chromatography (10% MeOH in DCM) to remove all the salts. After partial purification, 2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxahentetracont-40-yne (s-13e) was obtained as a brown oil that was taken on to the next step without full purification.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([F:13])([F:12])[F:11])[NH:9][NH:8]2)[CH:2]=1.C(N(CC)CC)C.ClOC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>C(O)C>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([F:11])([F:13])[F:12])[N:9]=[N:8]2)[CH:2]=1
Reactant: Cc1cccc(C2(C(F)(F)F)NN2)c1
Agent: CC(C)(C)OCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C2(C(F)(F)F)N=N2)c1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a cold stirring solution of 3-m-tolyl-3-trifluoromethyl-diaziridine (2.0 g, 10 mmol. prepared using the methods described in Doucet-Personeni C. et al., J. Med. Chem., 2001, 44, 3203 and Nassal, M. Liebigs Ann. Chem. 1983, 1510–1523 or in Stromgaard, K et al., J. Med. Chem., 2002, 45, 4038–46) in ethanol (20 mL) was added triethylamine (1.5 g, 15 mmol). To this mixture was added tert-butyl hypochlorite (3.25 g, 30 mmol), and the mixture stirred for 5 min. This mixture was poured into 10% aqueous sodium sulfite (100 mL), and extracted with ether. The ether extract was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, pentane) to provide 1.6 g (Yield 80%) of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm: 2.33 (3H, s) 6.90–7.03 (2H, m) 7.15–7.31 (2H, m).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[N:18][N:19](C5CCCCO5)[CH:20]=4)=[CH:14][N:13]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.O1CCOCC1>[N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:20]=[N:19][NH:18][CH:17]=4)=[CH:14][N:13]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(N3CCOCC3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2cn[nH]c2)c2c(N3CCOCC3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(morpholin-4-yl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C19) (4.0 g, 8.2 mmol) in dichloromethane (20 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 100 mL). The reaction mixture was stirred at room temperature for 2 hours, then poured into a mixture of ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 10% to 80% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 2.18 g, 5.44 mmol, 66%. LCMS m/z 401.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.78 (s, 2H), 7.19 (s, 1H), 5.64 (s, 2H), 3.56-3.66 (m, 6H), 3.34-3.40 (m, 4H), 0.91-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])=[CH:8][S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.O.[Pd]>[C:1]1([CH:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])[CH2:8][S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)C=C(CS(=O)(=O)O)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(O)CC(CS(=O)(=O)O)c1ccccc1

Procedure:
To 2-phenyl-propene-1,3-disulfonic acid (J. Amer. Chem. Soc., 66, 1105-9 (1944)) in THF-water (1:1) is added 10 wt % of 5% palladium on carbon and the mixture hydrogenated on a Parr shaker under 15 lb hydrogen pressure until the reaction is complete by thin layer chromatography (TLC). The mixture is filtered (Celite) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C@H:8]1[CH2:19][O:18][C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:33][Si](C(C)(C)C)(C)C)[CH:23]=[C:24]([O:25][Si](C(C)(C)C)(C)C)[C:15]=2[CH2:14][S:13][CH2:12][C@@H:11]([C:41]([O:43][CH3:44])=[O:42])[NH:10][C:9]1=[O:45]>>[CH:1]1([NH:7][C@H:8]2[CH2:19][O:18][C:17](=[O:20])[C:16]3[CH:21]=[C:22]([OH:33])[CH:23]=[C:24]([OH:25])[C:15]=3[CH2:14][S:13][CH2:12][C@@H:11]([C:41]([O:43][CH3:44])=[O:42])[NH:10][C:9]2=[O:45])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(=O)OC[C@H](N)C(=O)N1
Reactant: O=C1CCCC1
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)cc2C(=O)OC[C@H](NC2CCCC2)C(=O)N1

Procedure:
Operating in an analogues manner as described in Example 150, but replacing acetone by cyclopentanone, and using the product of Example 112 (a) as starting material, there was obtained methyl (4R, 7S)-7-(cyclopentylamino)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:6]([OH:8])=O)[CH3:2].[NH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:29][C:26]1[N:27]=[CH:28][C:23]([CH2:22][NH:21][C:6](=[O:8])[C:5](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:4][O:3][CH2:1][CH3:2])=[CH:24][CH:25]=1
Reactant: CCOCC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: NCc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOCC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 3-ethoxy-2-(4-trifluoromethylphenyl hydrazono) propionic acid (0.3 g, 1 mmol), 5-aminomethyl-2-chloropyridine (0.21 g, 1.5 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (0.29 g, 1.5 mmol) and chloroform (10 ml) was left at room temperature overnight. The mixture was extracted with chloroform, washed 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, dried on anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-3-ethoxy-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 170) (0.3 g, 0.72 mmol, 72%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O.O.C(OCC)C.[ClH:27]>C(#N)C.[Cu](Cl)Cl>[Cl:27][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1
Reactant: Cl
Reactant: Nc1nc2cc3c(cc2s1)OCO3
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: Clc1nc2cc3c(cc2s1)OCO3
Temperature: 25 °C

Procedure:
The product from Step 1 (1.7 g) was partially dissolved in dry acetonitrile (50 cm3) and added in portions to a stirred suspension of copper(II) chloride (1.41 g) and tert-butyl nitrite (1.56 cm3) in dry acetonitrile (15 cm3) at 60° C. The mixture was heated for 1 hr., cooled to ambient temperature, poured into water/diethyl ether and acidified with aqueous 2M hydrochloric acid. The aqueous fraction was separated and extracted with diethylether (3×100 cm3) and the combined organic fractions washed with water (3×50 cm3) and dried (magnesium sulphate). The solution was evaporated under reduced pressure to give a brown solid. The solid was fractionated by absorbing it onto silica and eluting with hexane/ethyl acetate (50:1 by volume) to give the required product as a colourless solid, M+ =213; 1NMR (CDCl3): δ7.36(1H,s): 7.14(1H,s); 6.08(2H,s); mp 131°-2° C.
Reaction SMILES: C(O)(=O)CCCCC(O)=O.C(#N)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].[C:19]([O:29][CH3:30])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].CO>>[C:16]([CH:15]([CH2:14][CH2:13][CH3:12])[C:24]([O:26][CH3:27])=[O:25])#[N:17].[C:24]([O:26][CH3:27])(=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:29][CH3:30])=[O:28]
Reactant: N#CCCCCC#N
Agent: O=C(O)CCCCC(=O)O
Solvent: COC(=O)CCCCC(=O)OC
Solvent: CO
Product: CCCC(C#N)C(=O)OC
Temperature: 220 °C
Reaction time: 5 h

Procedure:
Into a 2-liter, stainless autoclave were introduced 73.0 g (0.500 mole) of adipic acid, 432.0 g (4.000 moles) of adiponitrile and 26.1 g (0.150 mole) of dimethyl adipate. After purging with nitrogen, the content was stirred at 220° C. for 5 hours. After cooling the reaction mixture 320.0 g (10.000 moles) of methanol was added and the resulting mixture was stirred at 220° C. for 1 hour. By distilling the reaction mixture, there were obtained 114.2 g (0.810 mole) of methyl cyanovalerate and 26.8 g (0.154 mole) of dimethyl adipate.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:17]([C:19]1[N:24]=[CH:23][C:22]([NH:25][C:26]([CH2:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])=[CH:21][CH:20]=1)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:17]([C:19]1[N:24]=[CH:23][C:22]([NH:25][C:26](=[O:27])[CH2:28][CH:29]([CH3:34])[CH2:30][C:31]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:32])=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)nc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)nc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-ylamine (306.5 mg, 1.457 mmol) in DMF (7 mL) were added the compound obtained in Step 1 (300 mg, 1.215 mmol), HATU (554.14 mg, 1.457 mmol) and DIPEA (0.632 mL, 3.644 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (2×50 mL). The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (260 mg, 48.71%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21
Temperature: 95 °C

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 15 (0.96 g) is dissolved in DMF (7 mL), and K2CO3 (1.38 g) and 2-bromo-N,N-diethylethylamine hydrobromide (1.30 g) are added. The reaction mixture is heated to 95° C. for 16. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-3% MeOH/CHCl3) gave 0.373 g of the title compound which is crystallized from ethyl acetate to give 0.163 g of a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(OC)cc3)C2)nc1
Reaction time: 18 h
Yield: 77.6 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (350 mg) and 4-methoxybenzaldehyde (145 mg) in dichloromethane (5 ml) was added sodium triacetoxyborohydride (410 mg) at 20° C., and then it was stirred at the same temperature for 18 hours. The reaction was quenched with saturated aq NaHCO3 solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (11 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (362 mg) was obtained as colorless syrup.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[Br-:1].[NH2:17][C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: NC(=O)c1cccc(OCCCCCCBr)c1
Solvent: CC#N
Product: NC(=O)c1cccc(OCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Yield: 101.6 %

Procedure:
A mixture of 3-[(6-bromohexyl)oxy]benzenecarboxamide (2.10 g, 7 mmol, 1 equiv.) and triphenylphosphine (1.93 g, 7.35 mmol, 1.05 equiv.) in CH3CN (30 ml) was heated under reflux for 72 h. The solvent was evaporated under reduced pressure and the residue was triturated with dry Et2O until it solidified. The solid was filtered and dried in vacuo to give the desired compound as a white solid (4.0 g, 100%). HPLC-MS (method 1): m/z 482 [M−Br]+, Rt=3.65 min.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:52][S:53][CH3:54])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:52][S:53][CH3:54])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CSC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C(C)(C)O)nc(CSC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
A mixture of 300 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-methylthiomethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (d) above] and 5 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 1 hour. At the end of this time, the resulting solution was mixed with 5 ml of water and cooled with ice. The trityl alcohol which appeared as crystals was filtered off, and the filtrate was concentrated by evaporation under reduced pressure. Acetic acid and water in the residue were removed by distillation as azeotropic mixtures with toluene, to give 217 mg of the title compound as an amorphous powder.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O>[C:18]1([CH2:17][O:16][C:14]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Yield: 86.9 %

Procedure:
A suspension of L-glutamic acid (23.5 g; 160 mmol) in H2O (100 mL) was stirred, maintaining the pH at 8.5 with 10 M NaOH until complete dissolution. Benzyl chloroformate (35 g; 205 mmol) was added over 15 min to the clear solution. The mixture was stirred, maintaining the pH at 9 by adding 10 M NaOH until the reaction was complete. The cloudy mixture was washed with Et2O (3×150 mL) and then the pH of the resulting solution was adjusted to 2.1 with 1 M HCl. The cloudy aqueous mixture was extracted with Et2O (2×200 mL), the organic layers were collected and evaporated to yield the desired product (39.13 g; 139 mmol). Yield 87%.