Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 81.1 %

Procedure:
The same operation as in Example (227a) was performed using 4-[(tert-butoxycarbonyl)amino]piperidine (2.00 g, 9.99 mmol), benzyl chloroformate (2.14 mL, 15.0 mmol) and triethylamine (3.48 mL, 25.0 mmol), to obtain 2.71 g of the title compound as a white solid (81%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].Cl[CH2:6][O:7][C:8]([O:10][CH:11]([CH3:19])[CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9]>C1COCC1>[C:1]([O:4][CH2:6][O:7][C:8]([O:10][CH:11]([CH3:19])[CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C=C(C)C(=O)NCC(C)OC(=O)OCCl
Solvent: C1CCOC1
Product: C=C(C)C(=O)NCC(C)OC(=O)OCOC(C)=O
Reaction time: 120 h
Yield: 46.9 %

Procedure:
A THF solution (30 ml) of TBA acetate (1.21 g, 4 mmol), prepared by freeze-drying an aqueous solution of equimolar TBA-OH and acetic acid, was added to a stirred solution of N-(2-chloromethoxycarbonyloxypropyl) methacrylamide (0.943 g, 4 mmol) from Example 16 above in THF (10 ml) at room temperature. Following stirring for 5 days the solvent was removed under reduced pressure and the residue was dissolved in chloroform (50 ml) and washed with water (5×10 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography (silicagel, hexane/ethyl acetate (3:4)) gave 0.486 g (47%) of the title product.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:33])[CH:6]=[C:7]([CH3:32])[C:8](=[O:31])[C:9]=1[CH2:10][CH2:11][C@@:12]([OH:30])([CH3:29])[CH2:13][CH2:14][CH2:15][C@H:16]([CH3:28])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:2]=[CH2:3]>O=[Pt]=O.CCOC(C)=O>[OH:30][C@:12]([CH3:29])([CH2:13][CH2:14][CH2:15][C@H:16]([CH3:28])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][CH2:10][C:9]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([OH:33])[CH:6]=[C:7]([CH3:32])[C:8]=1[OH:31]
Reactant: C=CCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=CC1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCc1c(O)cc(C)c(O)c1CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
(R,R,R)-2-allyl-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-[1,4]benzoquinone (Ex-1E-4) (115 mg, 0.25 mmol) was hydrogenated using PtO2 (6 mg) at 50 psi for 3 h in a solution of EtOAc (7 mL). The suspension was filtered through silica, which was rinsed with EtOAc (40 mL). The solution was concentrated by rotary evaporation to yield (R,R,R)-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-2-propyl-benzene-1,4-diol (Ex-1E-5) as a clear, colorless oil (110 mg, 96%), which was carried on to the next step without further purification.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:30])[CH2:29][CH2:28]1>CC#N>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:32]([NH:31][C:23]2[CH:24]=[CH:25][C:26]([C:27]3([OH:30])[CH2:28][CH2:29]3)=[C:21]([F:20])[CH:22]=2)=[O:33])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C3(O)CC3)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 65.4 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (synthesis described for example A106) (0.104 mg, 0.348 mmol, 1.0 eq) in MeCN (8 mL) was added TEA (0.193 mL, 1.39 mmol, 4.0 eq) followed by addition of phenyl 3-fluoro-4-(1-hydroxycyclopropyl)phenylcarbamate (0.10 mg, 0.355 mmol, 1.02 eq) at RT and the mixture was stirred at reflux overnight. The solvents were evaporated and the crude product was purified by CC (eluent EtOAc/cyclohexane 1:2) to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(1-hydroxycyclopropyl)phenyl)urea (104 mg; 65%).
Reaction SMILES: [CH:1]([N:5]1[C:34]([CH2:35][CH3:36])=[C:8]2[N:9]=[C:10]([C:14]3[C:15]([O:31][CH2:32][CH3:33])=[N:16][CH:17]=[C:18]([S:20]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:19]=3)[NH:11][C:12](=[O:13])[C:7]2=[N:6]1)([CH2:3][CH3:4])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:47][O:48]CCO>>[CH:1]([N:5]1[C:34]([CH2:35][CH3:36])=[C:8]2[N:9]=[C:10]([C:14]3[C:15]([O:31][CH2:32][CH2:33][O:48][CH3:47])=[N:16][CH:17]=[C:18]([S:20]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH2:28]4)(=[O:21])=[O:22])[CH:19]=3)[NH:11][C:12](=[O:13])[C:7]2=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C(C)CC)nc2c(=O)[nH]1
Reactant: COCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCOC)[nH]c(=O)c2nn1C(C)CC
Temperature: 130 °C
Reaction time: 22 h

Procedure:
A solution of the title compound from example 4 (129 mg, 0.25 mmol) in 2-methoxyethanol (10 ml) was heated at 110° C. for 15 minutes, then cooled. Potassium bis(trimethylsilyl)amide (249 mg, 1.50 mmol) was added and the reaction stirred at 130° C. for 22 hours. The cooled mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and the layers separated. The organic phase was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluant to afford the title compound as a yellow foam, 59 mg.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N:35]1([CH2:41][CH2:42]O)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:42][CH2:41][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
Diisopropyl azodicarboxylate (0.48 mL, 2.4 mmol) was added dropwise to a stirred solution of 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.56 g, 2 mmol), 2-morpholin-4-yl-ethanol (0.24 mL, 2 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) in THF (20 mL) cooled to 0° C. The resulting solution was warmed to r.t. and stirred for about 16 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (ethyl acetate) to afford the final compound (0.50 g, 64%) as a clear oil
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28].ON1C2C=CC=CC=2N=N1.N=C=N.[N-]=C=O>CN(C)C=O.C(N(CC)CC)C>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH:28][C:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)[C:8]([CH3:20])=[C:9]2[CH3:19])=[O:18]
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)O)cc12
Reactant: CN(C)CCCN
Agent: N=C=N
Agent: On1nnc2ccccc21
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NCCCN(C)C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 8.9 mg portion of 1-(4-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, 3.1 mg of N,N-dimethylpropane-1,3-diamine, 4.1 mg of 1-hydroxybenzotriazole (HOBt) and 0.0083 ml of triethylamine were dissolved in 1.0 ml of N,N-dimethylformamide, and 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc., USA) was added, followed by overnight stirring at room temperature. Then, 50 mg of MP-Carbodiimide (Argonaut Technologies, Inc., USA) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc., USA) was added to the reaction liquid at room temperature, followed by stirring for 4 hours. Then, the reaction liquid was filtered. By concentrating the filtrate under a reduced pressure, 9.5 mg of N-[3-(dimethylamino)propyl]-(4-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxamide was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].BrCCCC[C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:11][CH2:12][CH2:14][CH2:16][N:29]2[CH:30]=[CH:31][N:32]=[CH:28]2)=[C:4]([NH2:20])[N:3]=1
Reactant: BrCCCCc1ncc[nH]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Reaction time: 8 h

Procedure:
2,6-Diamino-(9-β-D-ribofuranosyl)purine (5.0 g) in DMF (400 ml) was treated with sodium hydride (0.78 g). After stirring an additional 30 min a further portion of sodium hydride (2.6 g) was added immediately followed by bromobutyl-imidazole (9.9 g) in DMF (25 ml). The reaction mixture was stirred overnight and quenched with H2O. The reaction mixture was filtered through celite and evaporated to yield an oily product. TLC showed a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4]2[N:5]([CH:19]=[CH:20][N:21]=2)[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.[I:24]Cl>>[I:24][C:19]1[N:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=3)[CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[C:4]2=[N:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3n2)cc1
Reactant: ClI
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Yield: 98 %

Procedure:
Prepared from 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 10) (4.44 g, 14 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a yellow solid (5.803 g, 98%). MS (ISP) 458.2 [(M+H)+].
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:31]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([C:38]1[CH:39]=[CH:40][C:41]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(Oc2ccccc2)cc1
Yield: 50 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-phenoxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (50% yield); 1H-NMR (d6-DMSO) 1.24 (9H, s), 3.68 (2H, t), 4.09 (2H, t), 6.38 (1H, s), 6.96-6.98 (4H, m), 7.11 (1H, m), 7.21 (2H, d), 7.37 (2H, t); MS ES(+) 298.1 (M+-tBu). IR λmax=1697 cm−1.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:37][C:36]([O:35][CH3:34])=[O:39])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 120 h
Yield: 54.3 %

Procedure:
In DMF (15 mL) was stirred 4-hydroxy-1,3-benzenedicarboxylate dibenzyl ester (500 mg, 1.4 mmol) and potassium carbonate (276 mg, 2.0 mmol). To this was added methylbromoacetate (230 mg, 1.5 mmol) and the solution warmed to 50° C. and stirred 120 hours. The mixture filtered free of insoluble material and the DMF solution evaporated at reduced pressure to give a red oil. The oil was dissolved in ethyl acetate (50 mL) and washed successively with 10% citric acid (50 ML), saturated sodium bicarbonate solution (50 mL), and brine (50 mL). The organic phase dried over magnesium sulfate and evaporated at reduced pressure to give an oil. The oil was purified by MPLC (90 g silica gel, 2:1[hexane:ethyl acetate]) to give 330 mg (54%) of a clear oil. MS: M+1=435.2.
Reaction SMILES: CO[C:3](=O)[NH:4][CH2:5][CH2:6][CH:7]([OH:12])[CH:8]=[C:9]([CH3:11])[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O1CCCC1>[CH3:10][C:9]([CH3:11])=[CH:8][CH:7]([OH:12])[CH2:6][CH2:5][NH:4][CH3:3]
Reactant: COC(=O)NCCC(O)C=C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(O)C=C(C)C
Yield: 94 %

Procedure:
(±)-(3-Hydroxy-5-methyl-hex-4-enyl)carbamic acid methyl ester (38.9 g, 219 mmol) dissolved in tetrahydrofuran (150 mL) was added drop-wise to a refluxing solution of LiAlH4 (1M in tetrahydrofuran, 232 mL) maintaining reflux. After refluxing for 2 h. the mixture was cooled on an ice bath and 15% aq. sodium hydroxide (50 mL) was added drop-wise until a white precipitate separated out. The precipitate was filtrated and washed with tetrahydrofuran (2×200 mL), dichloromethane (2×200 mL) and diethylether (2×200 mL). The combined washes were evaporated. The resulting oil was redissolved in diethylether, dried (sodium sulfate), filtered and evaporated to give the crude product (29.5 g, 100%) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2.Br[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=1.O>CS(C)=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2
Reactant: Fc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Cn2c(-c3cccnc3)cc3cc(F)ccc32)cc1
Reaction time: 0.17 h

Procedure:
A flask is charged with NaH (0.284 g, 7.093 mmol) and DMSO (1.5 mL). 5-Fluoro-2-pyridin-3-yl-indole (Example 7, 0.112 g, 0.507 mmol) in DMSO (0.5 mL) is added. The flask and syringes are rinsed with DMSO (2 times 0.5 mL). After 10 min, ethyl 4-(bromomethyl)benzoate (0.192 g, 0.760 mmol) is added neat. After 10 min, water is added. The resulting precipitate is filtered through a sintered funnel and washed with water and dichloromethane to give 4-(5-fluoro-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm (sodium salt) 5.49 (s, 2H), 6.77 (s, 1H), 6.92 (d, J=8.1 Hz, 2H), 6.95-7.00 (m, 1H), 7.31-7.37 (m, 2H), 7.49 (dd, J=7.7, 5.2 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.87-7.92 (m, 1H), 8.56 (dd, J=4.9, 1.5 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 347.1212 [(M+H)+ Calcd for C21H16FN2O2: 347.1196].
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1>CO.O.CCOCC>[Cl:18][C:15]1[C:14]([CH:25]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[OH:26])=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: O=Cc1ccncc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CCOCC
Product: OC(c1ccncc1)c1nc(Cl)ccc1Cl
Temperature: -78 °C
Yield: 46.6 %

Procedure:
Under stirring at −78° C., t-butyl lithium (a 1.51M pentane solution: 4.6 ml) was added dropwise to an ether (20 ml) solution of 2,5-dichloropyridine (1.02 g, 6.89 mmol). After stirring at −78° C. for 2 hours, pyridine-4-carbaldehyde (0.65 ml, 6.89 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 hour. Water was then added to the reaction mixture. The temperature of the resulting mixture was raised to room temperature. The mixture was extracted with methylene chloride. The extract was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:50) eluate was concentrated under reduced pressure. The solid thus obtained was washed with ether and then collected by filtration to give the title compound (819 mg, 3.21 mmol, 47%) as a white powder.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:1](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CCO
Product: C(=Nc1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
Benzaldehyde (0.20 mole) was treated with aniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 minutes. The reaction mixture was left standing at room temperature for 10 min.; then it was placed in an ice-bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air-dried. Recrystallization from 85% ethanol gave N-benzylideneaniline. m.p. 50°-51.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28].O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:17][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[C:11]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-6-chloro-2-fluoro-benzoic acid benzyl ester (48, 1.20 g, 4.3 mmol) in methylene chloride (28 mL) was added pyridine (0.52 mL, 6.4 mmol) and propanesulfonyl chloride (0.685 g, 4.8 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated with silica gel column chromatography to give a colorless oil (49, 960 mg, 58.0%). MS (ESI) [M−H+]−=384.1.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N+:34]([C:37]1[CH:47]=[CH:46][C:40]([CH2:41][O:42][C:43](Cl)=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>O1CCCC1>[N+:34]([C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:24]=2)=[O:44])=[CH:46][CH:47]=1)([O-:36])=[O:35]
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 1-[4-aminobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and 0.4 g of Hunig base (=N-ethyldiisopropylamine) are dissolved in 15 ml of tetrahydrofuran. A solution of 0.75 g of chloroformic acid 4-nitrobenzyl ester in 5 ml of tetrahydrofuran is added dropwise thereto. The reaction solution is stirred for 3.5 hours at room temperature and for 2 hours at a bath temperature of 55°. The solution is concentrated by evaporation and the residue is taken up in methylene chloride and washed with water. Colourless crystals of 1-[4-(N-4-nitrobenzyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 146°-148° are obtained from alcohol.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH:11](Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1
Yield: 64.9 %

Procedure:
Ethyl acetoacetate (100 g, 0.77 mol) was dissolved in acetone (500 ml). To the thus obtained solution was added dibromoethane (361 g, 1.92 mol) and potassium carbonate (266 g, 1.92 mol) and the mixture was heated under reflux for 4 days. After filtering off insoluble matter, the filtrate was distilled under reduced pressure (80° C./8 mmHg) to obtain 78.1 g (65.1%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[N:15]\[NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)/[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].N.C[N:36]1C(=O)CCC1.Cl>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:36])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)Cl)c2)c1O
Reactant: CN1CCCC1=O
Agent: Cl
Agent: N
Solvent: CCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(N)=O)c2)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
(Z)-3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carbonyl chloride (5 g, 10.9 mmol) was added portion wise (over one hour) to an NH3/NMP solution (120 mL) and the resulting reaction mixture was cooled to 0° C. The cooled reaction mixture was stirred for one hour, then warmed to room temperature and EtOH (50 mL) was added followed by drop wise addition of 4 M HCl (100 mL). The resulting orange suspension was stirred for half an hour, filtered, washed with 2×50 mL EtOH. The filtered orange crystals were suspended in EtOAc (50 mL) and refluxed for 4 hours, then cooled to room temperature and 20 mL of MeOH/H2O (1/1) were added. the resulting orange suspension was filtrated, washed with MeOH/H2O=1/1 (30 mL) and dried in vacuum oven (0 bar/50° C.) for four hours giving 2.54 g of fluorescent orange crystals of Z)-3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carboxamide (Yield: 50.9%; HPLC purity: 98%).