Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].CS(O)(=O)=O>O1CCCC1.C(OCC)C.C(OC(=O)C)C.C(=O)(O)[O-].[Na+]>[C:1]([CH2:3][NH:4][C:5](=[O:6])[CH:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)CC(OCc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CC(OCc1ccc(-c2ccc(N3CCNCC3)cc2)cc1)C(=O)NCC#N
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A solution of tert-butyl 4-{4′-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)methyl][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate (115 mg, 0.21 mmoles) in tetrahydrofuran (3.5 mL) was treated with methanesulfonic acid (30 μL, 0.4 mmoles). The same amount of acid was added 5 times at 1.5 hour intervals and stirred overnight. Acid addition was resumed and two more portions (30 μL, 0.4 mmoles) were added, with a 1.5 hour interval. The reaction was diluted with diethyl ether, ethylacetate, sat. aq. sodium bicarbonate. The phases were separated and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product was chromatographed (1% sat. aq. ammonium hydroxyde, 9% methanol, 90% dichloromethane) to obtain 77 mg N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-4-yl]methoxy}pentanamide, a yellowish solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[C:17]=2[O:21][CH3:22])[C:12]1=[O:25])(=[O:9])[CH3:8].O.[OH-].[Na+]>O1CCCC1>[OH:25][CH:12]1[C:13]2[C:18](=[C:17]([O:21][CH3:22])[C:16]([O:23][CH3:24])=[CH:15][CH:14]=2)[CH2:19][CH2:20][CH:11]1[NH:10][C:7](=[O:9])[CH3:8]
Reactant: COc1ccc2c(c1OC)CCC(NC(C)=O)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)CCC(NC(C)=O)C2O

Procedure:
To a suspension of 0.32 part of lithium aluminum hydride in dry tetrahydrofuran, there is added 1.6 parts of 3,4-dihydro-2-acetamido-5,6-dimethoxy-1(2H)-naphthalenone in small portions. After the addition has been completed, the mixture is further stirred for 20 minutes, at the end of which time water is added so as to decompose the lithium aluminum hydride. The mixture is rendered sufficiently alkaline by the addition of a 3N aqueous solution of sodium hydroxide and, then, extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. The chloroform is distilled off and the residue is treated with ethanol. The procedure gives crystals of 1-hydroxy-2-acetamido-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene. Melting point 184°-186° C.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].Br[C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br.O>[F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:21]2[CH:26]=[N:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](COC(F)F)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(C(=O)O)c1

Procedure:
A mixture of methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-benzoate (233 mg, 0.84 mmol), 5-bromo-2-methylsulfonyl-pyridine (CAS no. 98626-95-0) (200 mg, 0.84 mmol), cesium carbonate (549 mg, 1.69 mmol) and bromotris(triphenylphosphine)copper(I) (157 mg, 0.17 mmol) in DMA (5 mL) was stirred in a microwave reactor at 160° C. for 6 hours. Ethyl acetate (50 mL) and water were added and the aqueous layer was acidified and extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine, dried (MgSO4) and reduced in vacuo to give the desired compound (0.16 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].I[CH2:32][CH3:33]>O.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:32][CH3:33])=[O:16])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 1.96 g (7.39 mmol) of 4-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid in 25 mL, of DMF was added 4.43 g (32.1 mmol) of potassium carbonate and 3.00 mL (37.2 mmol) of iodoethane at 0° C. The mixture was warmed to 22° C. and stirred for about 16 h. The reaction was then diluted with 20 ml, of water and 100 mL of saturated NaHCO3. The mixture was extracted with DCM (3×200 mL) and the combined organics were washed with 100 mL of water, dried (MgSO4) and evaporated to give ethyl 4-(2-(tert-butoxycarbonylamino)ethyl)benzoate as a sticky off-white solid.
Reaction SMILES: [Mg].BrCC.C(C1CCC(C(C)(C)C)CC1)=O.[Cl-].[NH4+].[OH:19][CH:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]1)[CH2:21][CH3:22]>C(OCC)C>[OH:19][CH:20]([CH:23]1[CH2:24][CH2:25][CH:26]([C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:27][CH2:28]1)[CH2:21][CH3:22]
Reactant: CCC(O)[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: CC(C)(C)C1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Product: CCC(O)C1CCC(C(C)(C)C)CC1
Yield: 66 %

Procedure:
To a mixture of 24 g (1.0 mol) magnesium turnings and 100 ml anhydrous ethyl ether was added 109 g (1.0 mol) bromoethane. The resulting solution was heated under reflux for two hours. To the above solution, 109 g (0.9 mol) 1-formyl-4-t-butylcyclohexane was added dropwise over 1 hour. After addition, the mixture was heated under reflux for four hours, allowed to cool, and then added to 100 ml of a mixture of saturated ammonium chloride solution and ice. The mixture was extracted with ether (3×100 ml) and the extract washed with water, dried, concentrated, and distilled to give a 1:1 mixture of cis and trans-1-(1-hydroxypropyl)-4-t-butylcyclohexane: 116 g (66% yield); bp 89-95 (1 mm); mol wt 198 (ms); nmr 0.85 (12 H, s, methyl H), 3.1-3.9 (1H, broad, αH); ir, 3350, 1364, 970.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].P([O-])([O-])([O-])=O.Br[CH2:26][C:27]([OH:29])=[O:28].Cl>C(O)C>[C:27]([CH2:26][O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])([OH:29])=[O:28]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: O=C(O)CBr
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OCC(=O)O
Temperature: 25 °C
Reaction time: 240 h
Yield: 74.6 %

Procedure:
To a solution of 0.3 g (1.1 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 30 ml ethanol was added 30 ml 0.5M phosphate buffer pH 7.4. The mixture was added 0.9 g (6.5 mmol) bromoacetic acid and then stirred at 25° C. for 10 days. 4N hydrochloric acid was added to pH 1, and then the reaction mixture was evaporated in vacuo. The residue was stirred with water to give 0.27 g (74%) of 1-carboxymethyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 257° C. 1H-NMR (DMSO-d6): 8.2 (1H, s), 7.6 (1H, s), 4.8 (2H, s).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[OH:18])[CH2:14]2.C(N(CC)CC)C>C1COCC1>[O:7]=[C:8]1[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH:10]3[O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH2:14]2
Reactant: ClCCOCCl
Reactant: O=C1C2CC3CC(C2)C(O)C1C3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C2CC3CC(C2)C(OCOCCCl)C1C3
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of 2-chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 4-oxo-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 4-oxo-2-adamantanol was converted by 98.3 and that 2.56 g (9.8 mmol, isolation yield: 97.6%) of a colorless liquid which was the intended product was obtained at a selectivity of 99.3%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:33])=[CH:35][CH:36]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CCSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (1.4 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.5 g of the aimed compound.
Reaction SMILES: [CH:1]([C:3]1[C:8](I)=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:19]=2)=[N:11]1)=[O:2].[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[NH:41][N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CS(C)=O>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[N:41]([C:8]1[C:3]([CH:1]=[O:2])=[C:4]([N:10]3[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)=[N:11]3)[CH:5]=[CH:6][CH:7]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: N#Cc1cn(-c2cccc(I)c2C=O)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Reaction time: 1 h
Yield: 40 %

Procedure:
1-(2-Formyl-3-iodophenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (115 mg, 0.218 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (48 mg, 0.218 mmol), cuprous iodide (41.5 mg, 0.218 mmol) and sodium bicarbonate (36.6 mg, 0.436 mmol) were combined in 2 mL of DMSO. The mixture was thoroughly degassed with argon and stirred in an oil bath preheated to 100° C. for 1 hr. The mixture was extracted with dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate and filtered. Solvents were evaporated and the residue was purified by flash column chromatography using methanol in dichloromethane (0% to 5% in 16 minutes, 24 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile as a pale pink solid (54 mg, 40% yield). LC/MS clacd for C34H30FN7O4 (m/e) 619.23, obsd 620.0 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H), 3.56-3.76 (m, 8H), 6.61 br. s., 1H), 7.40 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.52 (dd, J=12.4, 1.8 Hz, 1H), 7.55-7.59 (m, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.78 (t, J=8.1 Hz, 1H), 8.16 (s, 1H), 8.32 (s, 1H), 9.97 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](F)=[O:26].Cl>CCOCC>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:26]
Reactant: COc1ccc(NCCCCCCCC(=O)O)cc1
Reactant: O=C(F)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(N(CCCCCCCC(=O)O)C(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6.1 g (23 mmol) of 8-(4-Methoxyphenylamino)-caprylic acid are dissolved in 40 cc. of 0.2 n soda lye. A solution of 4.4 g (23 mmol) of 3-(Trifluoromethyl)-benzoic acid fluoride in 50 cc. of ether are added thereto within 20 minutes with vivid stirring dropwise at 25° C., holding the pH at between 7.2 and 8 by the dropwise addition of 0.2 n soda lye. After the addition, vivid stirring is continued for 30 minutes. The mixture is then acidified to pH 3 by the addition of 2 n hydrochloric acid. The aqueous and ethereal layers are separated. The aqueous phase is extracted several times with ether and then is rendered alkaline by the addition of calcium hydroxide. The separated calcium fluoride is filtered off with suction and is discarded. The purified ethereal phase is shaken with water, dried over MgSO4 and the solvent is distilled off. The residue is purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.[CH3:17][O:18][CH:19]=[CH:20][CH:21]=[CH2:22].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:17][O:18]/[CH:19]=[CH:20]/[CH:21]1[CH2:22][C:3]2[CH:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)[CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: C=CC=COC
Reactant: N#Cc1ccc(-c2ccc(O)c(I)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CO/C=C/C1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Temperature: 23 °C
Yield: 549.9 %

Procedure:
A solution of Example 1A (0.20 g, 0.623 mmol), 1-methoxybutadiene (0.18 g, 2.18 mmol), palladium diacetate (0.007 g, 0.031 mmol), sodium bicarbonate (0.261 g, 3.11 mmol) and tetrabutyl ammonium chloride (0.173 g, 0.623 mmol) was heated at 60° C. in DMF (3 mL) under an atmosphere of nitrogen for 36 hours. The reaction was cooled to 23° C., diluted with CH2Cl2 (50 mL), filtered through Celite. The solution was concentrated under reduce pressure and the residue was purified on silica using CH2Cl2 to give the titled compound (0.95 g, 55%). 1H NMR (CDCl3): 3.05 (m, 1H), 3.40 (m, 1H), 3.60 (s, 3H), 5.00 (m, 1H), 5.22 (m, 1H), 6.72 (d, J=14 Hz, 1H), 6.83 (d, J=7 Hz, 1H), 7.38 (m, 2H), 7.65 (m, 4H); MS (DCI): 278 (M+H+), 295 (M+NH4+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOCCOC.[S:21](=O)(=[O:24])([OH:23])[OH:22].CO>O.C1(C)C=CC=CC=1>[S:21]([OH:24])([O:11][CH2:10][CH2:9][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: OCCNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: COCCOCCOC
Product: O=S(=O)(O)OCCNCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-benzylethanolamine (302 g) in a mixture of water (8.92 ml) and toluene (1510 ml) and diglyme (151 ml) was added dropwise sulfuric acid (128 ml) over 30 minutes, and the mixture was stirred under reflux for 6 hours. After cooled to room temperature, to the mixture was added methanol (300 ml), and then the mixture was stirred for 1 hour. The precipitate was filtered and washed with methanol (300 ml×4), and dried to give 2-(N-benzylamino)ethyl hydrogen sulfate (352.6 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.CN(C)C>[F:1][C:2]1[N:3]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:4]=[CH:5][N:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ncc[nH]1
Agent: CN(C)C
Solvent: ClCCl
Product: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 80.2 %

Procedure:
To a solution of 2-fluoroimidazole (4.45 g.) in CH2Cl2 (100 ml.) and trimethylamine (7.93 ml.) was added triphenylmethyl chloride (14.4 g.) and the mixture was stirred for 2.5 hours. The solution was washed with water and brine, dried (MgSO4), treated with decolourising charcoal, filtered and evaporated. The solid residue was triturated with ether followed by methanol to give 2-fluoro-1-triphenylmethylimidazole (13.6 g.), m.p. 182°-185°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1.CCOCC.O>[OH:16][CH:15]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)[C:14]([CH3:18])([CH3:17])[CH3:13]
Reactant: CC(C)(C)C=O
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(O)c1cncnc1
Temperature: -120 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
225 g of 5-bromopyrimidine were dissolved in 1.5 liters of absolute tetrahydrofuran/1,000 ml of absolute ether, and the solution was cooled to -120° C. 250 ml of 50% strength n-butyl-lithium (in n-hexane) were added dropwise to the solution, during the course of 2 hours, at an internal temperature of -105° to -115° C. The mixture was further stirred for 1 hour at this temperature. 309 ml of trimethylacetaldehyde was then added dropwise during the course of 2 hours. The reaction mixture was then further stirred for 4 hours at this temperature. The reaction mixture was allowed to warm up to room temperature overnight, and 83 g of ammonium chloride, dissolved in a minimum quantity of water, were then added to it. The aqueous phase was separated off, and the organic phase was washed twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. 155 g (56% of theory) of 5-(1-hydroxy-2,2 -dimethylpropyl)pyrimidine of melting point 94°-96° C. were obtained after recrystallization of the residue from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:25](=[O:26])[O:27][CH2:28][CH3:29]
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC

Procedure:
This compound was obtained according to the same procedure as that described in Example 199 by acylation of (4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone with ethyl chloroformate. The product is purified by flash chromatography on silica, eluting with dichloromethane. A yellow powder is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[C:38]([NH2:39])=[CH:37][CH:36]=[C:35]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[N:34]=2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC=CC=1.CN(C=O)C>[CH3:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]2[C:38]([NH:39][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[CH:37][CH:36]=[C:35]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[N:34]=2)[CH2:31][CH2:32]1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3)ccc2N)CC1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2nc(N3CCN(C)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
A flask was charged with 4-cyano-pyrrole-2-carboxylic acid (as prepared in Example 2, 200 mg, 1.43 mmol), dichloromethane (30 ml), DMF (150 μL), and oxalyl chloride (275 μL, 1.60 mmol) and the mixture was stirred for 20 min at RT. Toluene (10 mL) was then added and the solvents were removed in vacuo. To the resulting acid chloride, dichloromethane (30 mL), DIEA (750 μL, 4.30 mmol), and 4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (as prepared in Example 55, step (c), 385 mg, 1.33 mmol) were added and the mixture was stirred at RT for 4 days. The mixture was poured into saturated aq sodium bicarbonate (100 mL), and extracted with dichloromethane (2×25 mL) and the solvents were removed in vacuo. Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane, then repurification by alumina preparative TLC eluting with dichloromethane-acetonitrile-methanol (7:2.5:0.5) yielded 38 mg (7%) of the title compound as a green solid. 1H-NMR (400 MHz, CDCl3): δ 11.32 (br s, 1H), 8.33 (d, 1H, J=8.8 Hz), 7.44 (s, 1H), 6.87 (s, 1H), 6.39 (d, 1H, J=8.8 Hz), 3.54 (m, 4H), 3.18-3.15 (m, 2H), 2.84 (m, 2H), 2.56 (m, 4H), 2.38 (s, 3H), 1.82-1.79 (m, 2H), 1.56 (m, 1H), 1.40-1.33 (m, 2H) 1.06 (d, 3H, J=6.5 Hz). LC-MS (ESI, m/z): Calcd. for C22H30N7O, 408.2 (M+H); found: 408.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]([NH:29][CH2:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([O-:36])=[O:35])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].[Cs+]>>[C:19]([NH:29][CH2:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:35])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(CCCCCCCBr)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
This compound was prepared from the product of 10a (0.79 g; 2.5 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The reaction time was 2 days. The crude product was purified on a 80×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. Fractions containing the product (3-6) were collected, and after evaporation 0.83 g (67%) product was obtained (amber oil that solidified to a waxy solid on standing in the freezer, mp 52-54° C.).