Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: COc1ccccc1B(O)O
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: CC#N
Solvent: O
Product: COc1ccccc1-c1nc2c(C)cccc2cc1C=O
Yield: 90.1 %

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline 3-carbaldehyde (0.206 g, 1 mmol), 2-methoxyphenyl boronic acid (0.167 g, 1.1 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.058 g, 0.05 mmol, 0.05 eq), and sodium carbonate (0.530 g, 5 mmol, 5 eq) in acetonitrile (7.5 mL) and water (2.5 mL). After purification, 2-(2-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (0.250 g, 90%) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.86 (1H, s), 8.88 (1H, s), 8.13 (1H, d, J=8.1 Hz), 7.85 (1H, d, J=7.1 Hz), 7.56-7.74 (3H, m), 7.22-7.30 (2H, m), 3.78 (3H, s), 2.80 (3H, s) Mass Spectrum (ESI) m/e=278.0 (M+1)
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([OH:18])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH:13]([O:18][CH3:33])[C:12]=3[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(O)CCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)C(OC)CCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Racemic ethyl 1-(biphenyl-4-ylmethyl)-5-hydroxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Example 17, 174 mg, 0.431 mmol) was dissolved in degassed N,N-dimethylformamide (2 mL), cooled to 0° C. under an atmosphere of nitrogen and treated with sodium hydride (19 mg, 0.47 mmol, 60% dispersion in mineral oil, 1.1 equiv) and then methyl iodide (0.096 mL, 1.55 mmol, 3.6 equiv). After stirring for 15 min, the mixture was warmed to ambient temperature and stirred for an additional 1 hr. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo to provide racemic ethyl 1-(biphenyl-4-ylmethyl)-5-methoxy-4-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[CH:14]=O.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]3=[N:1][C:16]4[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]=4[CH:14]=[C:3]3[CH:4]=[N:5]2)=[CH:12][CH:11]=1
Reactant: Nc1c(C=O)cnn1-c1ccc(F)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 100 °C
Yield: 70 %

Procedure:
A flask was charged with 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (111, R1=4-Fluorophenyl) (58.15 g, 283 mmol, cyclohexane-1,3-dione (47.7 g, 425 mmol) and toluene (600 mL). The slurry was stirred then pTSA (4.8 g, 25.2 mmol) was added. The mixture was warmed in an oil bath heated to about 100° C. for about 1 h. The mixture was allowed to cool to rt and stir overnight. The mixture was concentrated to dryness under reduced pressure. Water (400 mL), sat. aq. NaHCO3 (50 mL) and ethanol (100 mL) were added to the mixture. The supernatant was decanted and the solids were triturated with water (100 mL). The supernatant was decanted and the process repeated with another portion of water (100 mL). The solids were dried under reduced pressure to remove residual water. The material was stirred with MeOH (160 mL) then the solids were collected by filtration and washed with MeOH (80 mL). The material was dried under vacuum at about 65° C. to yield 1-(4-fluorophenyl)-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (112, R1=4-Fluorophenyl) (55.5 g, 70%); LC/MS, method 3, Rt=2.37 min, MS m/z 282 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.56 (s, 1H), 8.32-8.23 (m, 2H), 7.51-7.39 (m, 2H), 3.22 (t, J=6.2 Hz, 2H), 2.76-2.69 (t, J=6.0 Hz, 2H), 2.20-2.11 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH2:20][OH:21])[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH:20]=[O:21])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(C=O)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (180 mg, 0.6 mmol) in dichloromethane (10 mL) was added pyridinium chlorochromate (260 mg, 1.2 mmol) in portions. After being stirred at room temperature for 3 hours, the resulting dark mixture was diluted with diethyl ether, and stirred at room temperature for 10 minutes. The mixture was filtered through a short silica gel column. The filtrate was concentrated in vacuo to give 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (165 mg, 93%) as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.31 (s, 1H), 8.16 (s, 1H), 8.00 (dd, J=8.84, 5.56 Hz, 1H), 7.73 (dd, J=10.48, 2.40 Hz, 1H), 7.55 (d, J=6.82 Hz, 2H), 7.39-7.49 (m, 2H), 7.32 (td, J=8.65, 2.65 Hz, 1H), 4.99 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[F:16])=[N:7][C:6]2[NH:17][N:18]=[C:19]([CH3:20])[C:5]=2[C:4]=1[C:21](O)=[O:22])#[N:2].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[F:16])=[N:7][C:6]2[NH:17][N:18]=[C:19]([CH3:20])[C:5]=2[C:4]=1[C:21]([N:27]1[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]1)=[O:22])#[N:2]
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c(C(=O)O)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To 200 mg (0.57 mmol) of 5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid diluted in 4 ml of anhydrous dimethylformamide are added at 0° C. 121 mg (0.57 mmol) of tert-butyl piperazine-1-carboxylate, 76 mg (0.62 mmol) of N,N-dimethylpyridine-4-amine (DMAP), 110 mg (0.62 mmol) of N,N-dimethyl-N-[(methylimino)methylene]propane-1,3-diamine hydrochloride (EDCI) and 84 mg (0.62 mmol) of 1H-benzo[d][1,2,3]triazole-1-ol (HOBT). The reaction mixture is stirred 20 h at room temperature. The solvent is concentrated, water is added and the product extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5 to 3:7) to yield 158 mg of tert-butyl 4-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl)piperazine-1-carboxylate in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:21])=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)#[N:25]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.53 g (1.67 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil. MS (+FAB method): m/z (rel. int. [%])=598 ([M+H]+, 6), 109 (100); IR (KBr): 2163 cm-1 (C≡N); C27H36FN11S2 (597.80).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl[C:12]([C:14]12[N:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2)=O.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:12]([C:14]34[N:20]([C:21]([O:23][CH2:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[O:22])[CH:17]([CH2:16][CH2:15]3)[CH2:18][CH2:19]4)=[N:1][C:2]=2[CH:6]=1
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)Cl)CC2
Reactant: NC(=O)c1sc(Br)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C2CCC1(c1nc3cc(Br)sc3c(=O)[nH]1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, the crude product (2.0 mmol) of benzyl 1-(chlorocarbonyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate produced above and tetrahydrofuran (10 mL) was added N-ethyl-N-(1-methylethyl)propan-2-amine (0.70 mL) at room temperature. After stirring for 1 hr, the reaction system was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added ethanol (10 mL) and 2M sodium hydroxide (2.5 mL), and the mixture was stirred at 100° C. overnight. The reaction system was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (313 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)[C:9]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[CH:22]=[CH:24][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: Cc1ccc(-c2cccn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a brown powder (yield 13%), melting at 183-184° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCN1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
L-Proline (2.5 g, 22 mmol) is dissolved in NaOH (5%, 25 ml, 31 mmol) and, after cooling, treated dropwise, with vigorous stirring, with 4-fluorobenzoyl chloride (3.17 g, 20 mmol). The resulting suspension is again treated with NaOH (5%, 15 ml, 19 mmol) and stirred at RT for 1 h. HCl (20% strength, 10 ml) is added with ice cooling and the mixture is stirred until formation of a crystallizate which can be filtered off with suction. The crystallizate subsequently filtered off with suction is washed with water until HCl-free and dried over P2O5 in a desiccator. 4.21 g (88.8% of theory) of crystallizate remain after drying.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:42]([F:45])([F:44])[F:43]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:32]=[CH:31][C:30]=2[C:42]([F:43])([F:44])[F:45])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1ccc(Oc2ccccc2)cc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2cc(Oc3ccccc3)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(100 mg, 0.448 mmol) in dry THF (6.0 ml) under nitrogen at ambient temperature was added 1.0 M lithium bis(trimethylsilyl)amide (0.45 ml, 0.45 mmol) dropwise and then the solution stirred for approximately 30 min. To the solution was added a solution of crude 2-(bromomethyl)-4-(phenyloxy)-1-(trifluoromethyl)benzene (0.135 g) in dry THF (2.5 ml) and stirred for 7 h. The solvent was removed using a stream of nitrogen. To the residue was added saturated aqueous sodium bicarbonate (approximately 7 ml) and then the residue extracted three times with chloroform. The combined organic extracts were filtered through a hydrophobic frit. The solvent was removed in vacuo and the residue purified on MDAP (Method B). The appropriate fractions were combined and solvent evaporated in vacuo. The residue was dried under high vacuum at 45° C. to give the title compound as a white solid (85 mg); LCMS: (System 4) MH+=474, tRET=3.30 min.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1O>O1CCCC1>[C:1]1([CH:7]2[CH2:8][C:9](=[O:14])[C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[NH:15][C:11]=3[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: NC1CCCCC1O
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Temperature: 150 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 2-aminocyclohexanol (3.2 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were added 2-bromomesitylene (4.2 g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 4 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (3.4 g).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][CH2:17]Cl>C(#N)C.O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH2:15][O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COCCl
Reactant: Oc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COCOc1cccnc1F
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Fluoropyridin-3-ol (55 g, 486 mmol) and cesium carbonate (158 g, 486 mmol) were suspended in ACN (400 mL). A solution of chloromethyl methyl ether (40 mL, 527 mmol) in dry tetrahydrofuran (50 mL) was added dropwise via an addition funnel. After 1 hour additional MOM-Cl (5 mL) was added and the reaction stirred for another 2 h. The reaction was evaporated to dryness under reduced pressure and the residue partitioned between diethyl ether (400 mL) and water (500 mL). The organic was washed with saturated sodium bicarbonate (100 mL) then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to 1:1 hexane:DCM gradient) to give the desired 2-fluoro-3-(methoxymethoxy)pyridine (53.5 g, 340 mmol, 70.0% yield).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([N:24]([C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][N:41]([CH:44]5[CH2:47][O:46][CH2:45]5)[CH2:40][CH2:39]4)=[CH:34][CH:33]=3)C(=O)OC(C)(C)C)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[CH:20]=2)[CH:12]=[N:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([NH:24][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:43][CH2:42][N:41]([CH:44]5[CH2:47][O:46][CH2:45]5)[CH2:40][CH2:39]4)=[CH:36][CH:37]=3)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[CH:20]=2)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cncc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (6-(6-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)imidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate XVI (200 mg, 0.269 mmol) in DCM (2 ml) was added TFA (0.5 ml, 6.578 mmol). The reaction was stirred at rt for 16 h, saturated sodium bicarbonate was added, extracted with EtOAC and purified on silica gel, eluted with 5% MeOH/EtOAc, 20% MeOH/EtOAc. The desired fractions were combined and concentrated to provide the title compound 2. LCMS-ESI+ (m/z): [M+H]+: 444.2. 1H NMR (300 MHz d6-DMSO) δ: 9.5 (s, 1H), 8.588 (s, 1H), 8.47 (s, 1H), 8.12 (d, 1H), 7.95-7.92 (d, 2H), 7.88 (s, 1H), 7.62 (s, 1H), 6.99-6.96 (d, 2H), 6.46 (s, 2H), 4.57-4.53 (m, 2H), 4.48-4.44 (m, 2H), 3.43 (m, 1H), 3.15-3.12 (m, 4H), 2.41-2.38 (m, 4H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[N:7][C:6]=1[CH3:29])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:10]([N:9]1[C:5]([CH2:4][NH2:1])=[C:6]([CH3:29])[N:7]=[CH:8]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-azidomethyl-4-methyl-1-tritylimidazole (3.0 g, 7.9 mmol) in THF (70 ml) was added triphenylphosphine (5.18 g, 19.8 mmol). The resulting solution was refluxed for 1.5 h then water (5 ml) was added. Refluxing was continued for an additional 24 hours. After cooling to room temperature, the solvents were removed in vacuo and the crude reaction mixture was purified by chromatography on silica gel (19:1 chloroform/10% NH4OH in methanol) to give of the title compound. 1H NMR (CDCl3) d 1.40 (s, 3 H), 1.70 (br s, 2 H), 3.70 (s, 2 H), 7.10-7.35 (m, 16 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[N:35]1([CH2:40][CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[N:51]2[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:39]=[CH:38][N:37]=[CH:36]1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:43]3[N:42]([CH2:41][CH2:40][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1ccnc1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3CCn3ccnc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 66.1 using 1-(2-methoxy-5-(1h-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.40 g, 0.84 mmol) and 4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.48 g, 0.84 mmol) to give the title compound: Rf=0.18 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: C(O)(=O)C.[C:5]1([C:11]2[CH:20]=[C:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Pt]=O>[C:5]1([C:11]2[CH:20]=[C:19]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-c2cc(CCc3ccccn3)c3ccccc3n2)cc1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(-c2cc(CCC3CCCCN3)c3ccccc3n2)cc1

Procedure:
4.55 ml of concentrated acetic acid are added to a solution containing 2.5 g of 2-phenyl-4-[2-(2-pyridyl)-ethyl]-quinoline in 250 ml of ethanol, then 0.5 g of 82% platinum oxide is added as catalyst. Hydrogenation is effected at 30° C., under a hydrogen pressure equal to the normal pressure for 6 hours, at the end of which time 700 ml of hydrogen have been absorbed. The catalyst is eliminated by filtration. The ethanol is evaporated under reduced pressure and the residue is taken up with 200 ml of water. The aqueous phase is made alkaline by means of concentrated ammonia, and extracted with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is fixed on a column of 200 g of silica and eluted with a 9/1 toluene-diethylamine mixture. 0.65 g are thus isolated of 2-phenyl-4-[2-(2-piperidyl)-ethyl]-quinoline in the form of an oil. This compound is dissolved in acetone and converted, by addition of hydrochloric acid, to its dihydrochloride, which melts at 200° C.