Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](=[O:15])([O:12][CH2:13][CH3:14])N>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2].C(O)C>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[C:6]([NH:8][C:10]([O:12][CH2:13][CH3:14])=[O:15])[CH:5]=[CH:4][C:3]=1[CH3:9])=[O:15])[CH3:14]
Reactant: Cc1ccc(N)cc1N
Reactant: CCOC(N)=O
Agent: CCCCCCCC(=O)[O-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Reaction time: 6.1 h

Procedure:
733 g of 2,4-diamino-toluene, 1069 g ethyl carbamate, 1160 g ethanol (approximately 96%) and 5.5 g zinc octoate were reacted in the apparatus described in Example 1 for 6.1 hours at 200° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography (HPLC). A yield of 1220 g (76% of the theoretical yield) of 2,4-bis-(ethoxy carbonylamino)-toluene was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:46])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:46])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(CCO)CC4)cc3)cc12
Yield: 2.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)ethanol (200 mg, 0.259 mmol) was hydrolyzed by lithium hydroxide (108 mg, 2.59 mmol), THF/Methanol/water (5/5/2.5 ml) to yield 3 mg (2.2% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.34 (s, 1H), 7.75-7.74 (d, 1H), 7.44-7.41 (m, 2H), 7.28-7.27 (m, 2H), 7.00-6.7 (m, 4H), 6.52-6.51 (d, 1H), 5.26 (s, 2H), 3.73-3.69 (t, 2H), 3.26 (m, 4H), 2.91 (m, 4H), 2.79-2.77 (t, 2H), 2.12-2.08 (m, 6H). MS: m/z=525.2 (M+1), HPLC: 80.69% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:34])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(=O)O)s4)c3c2)CC1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a mixture of 0.048 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid, 0.046 g (0.12 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.008 g (0.15 mmole) of ammonium chloride and 1 mL of dimethylformamide was added 0.052 mL of diisopropylethylamine. The mixture was stirred at ambient temperature for 1 hour, filtered and then purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.027 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.2) as a white solid. MH+/Z=467
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([CH3:41])[C:31]=1[N:32]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[N:33]1)[O:5][CH:6]([CH:23]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24]1)[C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])=[CH:9][CH:8]=1.O.O1CCCC1.[OH-].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1.CO>[CH3:41][C:30]1[CH:29]=[C:4]([CH:3]=[C:2]([CH3:1])[C:31]=1[N:32]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[N:33]1)[O:5][CH:6]([CH:23]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24]1)[C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(c2ccc(C(=O)NCCC(=O)O)cc2)C2CC(C)(C)C2)cc(C)c1-n1cc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
To a flask containing ethyl 3-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoate (100 mg, 0.180 mmol) was added water (0.437 mL), tetrahydrofuran (0.437 mL), and methanol (0.437 mL). Sodium hydroxide (36.1 mg, 0.880 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 108 mg of crude material. The crude material was azeotrophed three times with toluene and three times with methylene chloride and then dried in vacuo for 18 h to provide (+/−)-3-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoic acid (99.0 mg, 100%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.76 (t, J=6.2 Hz, 1H), 6.56 (s, 2H), 5.01 (d, J=7.0 Hz, 1H), 3.72 (q, J=5.9 Hz, 2H), 2.74-2.59 (m, 3H), 1.88 (s, 6H), 1.87-1.68 (m, 3H), 1.68-1.58 (m, 1H), 1.13 (s, 3H), 1.10 (s, 3H). MS (M+1): 544.3.
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.II.[Br:24]Br>>[Br:24][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:11]([OH:13])=[O:12])=[CH:3][CH:2]=[C:1]2[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Reactant: BrBr
Agent: II
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(C(=O)O)c2c(Br)cccc12

Procedure:
44 parts of naphthalene-1,4-dicarboxylic acid are introduced in portions into 900 parts of concentrated sulphuric acid and the mixture is stirred to give a homogeneous suspension. A few crystals of iodine and 36 parts of bromine are then added and the whole is stirred overnight at room temperature. For working up, the mixture is discharged onto ice and filtered and the product is washed with water until neutral. 8-Bromo-naphthalene-1,4-dicarboxylic acid, which is thus obtained, can be purified by recrystallisation from glacial acetic acid. Melting point 288°-290°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.O1CCCC1.[Pd]>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of 5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (260 mg, 0.97 mmol) in ethanol (10 mL) and tetrahydrofuran (5 mL) was added 10 wt % palladium on carbon (100 mg). The reaction was pressurized to 50 psi hydrogen and stirred at room temperature for 4 hours. The reaction was filtered through Celite and concentrated to give 6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (220 mg, 95%). 1H NMR (400 MHz, CD3OD, δ): 7.98 (s, 1 H), 7.88 (d, 2 H), 7.60 (d 2 H), 7.54 (d, 1 H), 7.09 (d, 1 H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:16])[C:12](OC)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:16])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 96.5 %

Procedure:
8.4 g (0.204 mole) of sodium borohydride was suspended at room temperature in a solution of 35.8 g (0.17 mole) of the methyl (R)-(+)-2-(1-isobutoxyethoxy)propionate (obtained in Reference Example 5) dissolved in 170 ml of toluene. Thereto was dropwise added slowly 40.8 ml (1.02 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours to give rise to a reaction. To the reaction mixture was added 50 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to re-extraction with 50 ml of toluene. The two organic layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 28.9 g (yield: 98.0%) of an oily title compound (diastereomixture).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](O)=[O:6].S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([Cl:22])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CCBr)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCBr)(c1ccccc1)c1ccccc1

Procedure:
4-Bromo-2,2-diphenylbutyric acid (Compound B(1), 23 g, 72 mmol) was suspended in 150 mL of chloroform, and 20 mL of thionyl chloride (270 mmol) was added dropwise. After addition of the thionyl chloride, 0.2 mL of dimethylformamide was added and the resulting solution heated at reflux for about 4 h. The reaction mixture was then concentrated under reduced pressure to provide 4-bromo-2,2-diphenylbutyric chloride (Compound D(1)) as a pale yellow oil that was used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C.C(Cl)(Cl)Cl>[NH2:18][C:14](=[O:17])[CH2:15][CH2:16][N:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][C:2]([CH3:13])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(N)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCC(N)=O)CC1

Procedure:
A molten mixture of 7.5 (0.04 mole) of 1-(1,1-dimethylethoxycarbonyl)piperazine, 2.9 g (0.04 mole) of acrylamide and 3 drops of acetic acid was stirred and heated at 65° for 18 hours. The mixture which had solidified during the heating period was dissolved in 100 ml of chloroform and washed with dilute aqueous sodium hydroxide solution. The dried (MgSO4) CHCl3 solution was filtered and evaporated in vacuo to yield a white solid. Recrystallization from toluene-hexane returned 8.0 g (78%) of product, m.p. 96°-8°. Calc. for C12H13N3O3 (257.335): C, 56.01; H, 9.01; N, 16.33. Found: C, 56.05; H, 9.04; N, 16.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([OH:18])[O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:39][CH2:40][CH2:41][CH2:42]O>ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]2[CH2:17][CH2:16][CH:15]([O:18][CH2:42][CH2:41][CH2:40][Br:39])[O:14]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: OCCCBr
Reactant: COc1cc(C2CCC(O)O2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(C2CCC(OCCCBr)O2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Compound 105 (1.0 g, 3.94 mmol) was dissolved in 4 mL dichloromethane. Triethylamine (597 mg, 5.90 mmol) was added to this solution. The reaction mixture was cooled with an ice bath and trifluoroacetic anhydride (1.24 g, 5.90 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and then 3-bromopropanol (1.84 g, 13.27 mmol) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to an oil which was purified by column chromatography (silica, 4:1 hexane/ethyl acetate) (128: 430 mg and its cis isomer 250 mg; total yield 46%). 1H NMR (CDCl3): 128 (trans): 1.77(m,1H); 1.98(m,1H); 2.15(m,2H); 2.20(m,1H); 2.40(m,1H); 3.53(t,2H); 3.60(m,1H); 3.83(s,3H); 3.87(m,1H); 3.89(s,6H); 5.01(t,1H); 5.35(dd,1H); 6.57(s,2H).
Reaction SMILES: S(O)(O)(=O)=O.[CH2:6]([N:8]([CH2:17][CH2:18]NS(C)(=O)=O)[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=1)[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH3:7][CH2:6][N:8]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=1)[CH2:17][CH3:18]
Reactant: CCN(CCNS(C)(=O)=O)c1ccc(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc(N)c(C)c1
Temperature: 25 °C

Procedure:
Into the mixture comprising 0.78 g of Comparative Coupler (C-2), 0.80 g of N-ethyl-N-(β-methanesulfonamidoethyl)-3-methyl-4-aminoaniline sulfate, 3.75 g of sodium carbonate, 60 ml of chloroform and 50 ml of water, a solution of 10 ml of water having dissolved therein 1.65 g of ammonium persulfate was gradually added with stirring at room temperature. After stirring the reaction solution for one hour, a chloroform layer was separated and the reaction solution was subjected to purification through silica gel column chromatography to obtain Azomethine Dye (CD-2). Further, Azomethine Dyes (D-1) to (D-4) were synthesized using the couplers of the present invention in place of Coupler (C-2). ##STR5##
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.Br[C:25]1[CH:26]=[C:27]([CH3:32])[CH:28]=[C:29]([CH3:31])[CH:30]=1>[Cu]I.O1CCOCC1>[CH3:32][C:27]1[CH:26]=[C:25]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: NC(=O)c1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C)cc(NC(=O)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 90.3 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (4.0 mg, 0.0210 mmol, 1.0 mol %), benzamide (300 mg, 2.48 mmol), K2CO3 (600 mg, 4.38 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (26 μL, 0.216 mmol, 11 mol %), 5-bromo-m-xylene (280 μL, 2.06 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 10–15 provided 419 mg (90% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 7.92–7.85 (m, 3H), 7.59–7.75 (m, 3H), 7.31 (s, 2H), 6.82 (s, 1H), 2.34 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 165.6, 138.7, 137.7, 135.1, 131.7, 128.7, 126.9, 126.3, 117.9, 21.3. IR (neat, cm−1): 3300, 1649, 1614, 1547.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:16][CH2:17][CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([NH:25][C:2]2[CH:7]=[C:6]([N:8]([CH2:16][CH2:17][CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:4][N:3]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCN(C(=O)OC(C)(C)C)c1cc(Cl)ncc1C#CCCCO
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCN(C(=O)OC(C)(C)C)c1cc(Nc2ccc(C#N)cc2)ncc1C#CCCCO
Temperature: 100 °C
Reaction time: 10 h
Yield: 15.7 %

Procedure:
To tert-butyl (2-chloro-5-(5-hydroxy-1-pentyn-1-yl)pyridin-4-yl)(propyl)carbamate (S10, 88 mg), 4-aminobenzonitrile (59 mg), tris(dibenzylideneacetone)dipalladium(0) (22 mg), 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (29 mg) and cesium carbonate (203 mg), 1,4-dioxane (2.5 mL) was added at room temperature, and the mixture was stirred at 100° C. for 10 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The insoluble matter was removed by filtration through Cerite. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain tert-butyl (2-((4-cyanophenyl)amino)-5-(5-hydroxy-1-pentyn-1-yl)pyridin-4-yl)(propyl)carbamate (S11, 17 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[CH:27]=[C:26]([CH2:28][NH2:29])[CH:25]=[C:24]([CH3:30])[N:23]=1>CCCCO>[CH3:21][C:22]1[CH:27]=[C:26]([CH2:28][NH:29][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:25]=[C:24]([CH3:30])[N:23]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cc(CN)cc(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(CNc2nc(F)nc3[nH]cnc23)cc(C)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.9 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (2,6-dimethylpyridin-4-yl)methanamine (0.54 g, 4 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.5 g (63%); δH CDCl3, 250 MHz) 2.48 (6H, s, 2×CH3), 3.65-3.54 (2 H, m, NHCH2), 4.61 (1 H, s, br, NH), 7.32 (2 H, s, ArH), 7.84 (1 H, s, ArH)), 9.05 (1 H, s, br, NH); δC (CDCl3, 250 MHz) 159.2 (C), 156.62 (C), 156.61 (C), 155.46 (C), 146.92 (CH), 136.3 (C), 122.05 (2×CH), 119.48 (C), 41.6 (CH2), 18.06 (2×CH3)
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:16])=[CH:13][CH:12]=1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(Cl)cc1)C(=O)O

Procedure:
Racemic tert-butylglycine and 4-chlorobenzoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]1([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>C1COCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([C:16](=[O:18])[CH2:17][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)C1CCCCC1
Reactant: N#Cc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(=O)C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
Add 4-iodobenzonitrile (1.0 g, 4.37 mmol) and 1-cyclohexyl-ethanone (717 mg, 5.68 mmol) to a suspension of tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), BINAP (98 mg, 0.157 mmol) and sodium tert-butoxide (546 mg, 5.68 mmol) in anhydrous THF (26 mL). Heat the mixture at 70° C. under nitrogen atmosphere. After 6 h, add tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), BINAP (98 mg, 0.157 mmol), sodium tert-butoxide (294 mg, 3.06 mmol) and 1-cyclohexyl-ethanone (386 mg, 3.06 mmol) and allow to stir the mixture at 70° C. under nitrogen overnight. Add water and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (92:8) to obtain the desired intermediate as a yellow oil (902 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[CH:18](=[N+:25]([CH3:27])[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:18]([N:25]([CH3:27])[CH3:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Clc1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(-c2ccc(Cl)cc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-chlorophenyl)-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:31](=[O:39])(=[O:38])[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=1>C(#N)C>[C:8]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:31](=[O:39])(=[O:38])[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S1(=O)c2ccccc2N(c2ccc(O)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(N2c3ccccc3S(=O)(=O)c3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.68 g (6.68 mmol) of triethylamine and 0.34 g (2.44 mmol) of benzoyl chloride were added to a solution of 0.72 g (2.22 mmol) of 10-(4-hydroxyphenyl)phenothiazine 5,5-dioxide in 120 ml of acetonitrile. After stirring at room temperature for 45 min, the solvent was distilled off. The residue was taken up in 100 ml of hot water and stirred at 75° C. for 30 min. The solid was filtered off with suction while hot, washed with hot water and dried at 120° C. in a forced-air drying cabinet. 0.87 g (92% of theory) of colorless microcrystals having an m.p. of 233-235° C. were obtained.