Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:39])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:39])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
1-{4-[4-(3,5-Dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (172 mg) described in Example 448 was dissolved in 1,2-dichloroethane (5 mL), trifluoromethanesulfonic acid (0.18 mL) was added, and the mixture was stirred at 80° C. for 30 min. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform/methanol (10:1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (92 mg).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCOC(C)=O.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1([CH3:20])[O:25][CH2:24][CH2:23][O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(CCCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1

Procedure:
A mixture of ketone 7-2 (695 mmol), ethylene glycol (59 ml, 1040 mmol), p-TSA (500 mg, 2.713 mmol) and benzene (2000 mL) was heated to reflux with azeotropic removal of water for 12 hours. The reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4), and concentrated to give 7-3 as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:55]=[CH:54][C:33]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(=O)CN(C)CC(=O)O3)=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:55][CH:54]=3)=[CH:42][CH:41]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
Pd(Ph3P)4 (76 mg, 0.066 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.329 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (94 mg, 0.362 mmol), potassium phosphate tribasic (524 mg, 2.47 mmol) in dioxane (2 ml) and water (0.5 ml) stirred in a screw-capped pressure vessel for 16 h at 80° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-20% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)acetate 139 mg (72%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.44-7.38 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.03-6.94 (m, 3H), 5.97 (br. s, 1H), 4.96 (dt, J=12.3, 6.3 Hz, 1H), 4.23 (t, J=6.6 Hz, 2H), 3.36-3.29 (m, 4H), 3.07 (t, J=6.6 Hz, 2H), 2.43 (s, 3H), 2.04 (s, 3H), 1.75 (t, J=11.4 Hz, 1H), 1.52-1.47 (m, 1H), 1.37 (br. s, 1H), 1.19 (d, J=6.2 Hz, 3H), 1.15-1.13 (m, 12H), 1.08-1.02 (m, 2H), 0.84 (d, J=5.1 Hz, 3H). UPLC (M+H)=591.56.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:24](O)[CH2:25][CH3:26]>>[CH2:24]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:22][CH:23]=1)=[O:3])[CH2:25][CH3:26]
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1
Reactant: CCCO
Product: CCCOC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 4--CH3 (CH2)2OOCC6H4 ], m.p. 54° C., from 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole (Example 16) and n-propyl alcohol; MIC vs. rhinovirus Type 2 in vitro=0.07 μg/ml.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][N:9]=1.O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3]([N:9]1[C:8]([NH2:7])=[C:16]2[C:11]([CH:12]=[C:13]([Cl:17])[CH:14]=[CH:15]2)=[N:10]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)n1nc2cc(Cl)ccc2c1N
Yield: 58 %

Procedure:
0.15 mol of dimethylcarbamic acid chloride is added dropwise, while stirring, to 0.1 mol of 3-amino-6-chloroindazole in 50 ml of pyridine, in the course of which the temperature rises to 45° C. After 11/2 hours, 250 ml of water are allowed to run in and the reaction product is isolated by filtration. After dissolving the product in chloroform, filtering off a by-product of melting point 237°-238° C and evaporating the solution, 3-amino-6-chloroindazole-2-carboxylic acid dimethylamide (melting point: 178°-180° C; 58% of theory) is obtained.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(OC([N:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22][CH2:21]1)=O)(C)(C)C.N1C(C)=CC=CC=1C>C(Cl)Cl.CO>[NH:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][S:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CSCc2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: c1ccc2c(c1)CSCN2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.47 ml of trimethylsilyl trifluoromethanesulfonate are added dropwise to a solution of 1.0 g of N-tert-butoxycarbonyl-3,4-dihydro-1H-2,4-benzothiazine in 35 ml of methylene chloride at room temperature, and 1.41 ml of 2,6-lutidine is added. The reaction mixture is stirred at room temperature for 20 minutes and then diluted with 5 ml of methanol and concentrated. The crude product is purified by means of FC (30 g of silica gel, mobile phase G). This gives the pure title compound: Rf (D)=0.26; Rt (I)=19.5 min; anal. calc. for C8H9NS: C 63.54%, H 6.00%, N 9.26%; found C 63.22%. H 6.01%, N 8.99%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH2:6][C:7](F)([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1)[NH2:4].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[CH:36]=[C:35]([C:37](O)=[O:38])[NH:34][C:30]2=[N:31][C:32]=1[CH3:33])=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH3:33][C:32]1[N:31]=[C:30]2[NH:34][C:35]([C:37](=[O:38])[NH:4][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=3)[C:2]([F:17])([F:16])[F:1])=[CH:36][C:29]2=[CH:28][C:27]=1[CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1nc2[nH]c(C(=O)O)cc2cc1CNC(=O)OC(C)(C)C
Reactant: NC(C1=CC=CC(F)(C(F)(F)F)C1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2[nH]c(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
2,2,2-Trifluoro-1-[3-fluoro-3-(trifluoromethyl)phenyl]ethanamine (726 mg, 2.98 mmol) was dissolved in N,N-dimethylformamide (10 ml), and 5-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (730 g, 2.39 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (907 mg, 2.39 mmol) and 4-methylmorpholine (725 mg, 7.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate and the extract was dried over sodium sulphate, adsorbed on silica gel and chromatographed with ethyl acetate. 420 mg (33% of theory) of tert-butyl {[6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate were obtained. HPLC-MS: log P=3.49; mass (m/z): 531.2 (M+H)+; 1HNMR (D6-DMSO): δ 1.40 (s, 9H), 3.30 (s, 3H), 4.20 (m, 2H), 6.29-6.32 (m, 1H), 7.35 (s, 1H), 7.71 (m, 1H), 7.82-7.84 (m, 1H), 8.03 (d, 1H), 8.17 (s, 1H), 9.43 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[C:23]([C:25]([CH3:37])([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])[CH3:26])#[N:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][C:25]([C:23]#[N:24])([CH3:26])[CH3:37])[CH:29]=4)[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(OC(C)(C)C#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (83 mg, 265 μmol) produced in Example D35(v), 3-(1-cyano-1-methylethoxy)benzoic acid (71 mg, 345 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (120 mg, 318 μmol) in pyridine (3 mL) was stirred at room temperature for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and hexane to give the title compound (61 mg, 46%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH:8]C(=O)C)[N:7]=1.[CH2:23]([Mg]Br)[CH3:24]>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:23]([C:2]1[C:3]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1)[CH3:24]
Reactant: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: CC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2 %

Procedure:
A mixture of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (63 mg, 0.2 mmol; the synthesis of which has been disclosed in WO 2006/135993) and iron tris(acetylacetonate) (10 mg, 0.028 mmol) in THF (2 ml) and NMP (1 ml) was added ethylmagnesium bromide (0.6 ml, 0.6 mmol; 1.0 M solution in THF). After stirring at room temperature for 10 minutes, the solution was diluted with THF and quenched by adding a solution of 0.2 N HCl. The mixture was extracted with ethyl acetate, then dried over Na2SO4 and concentrated. The residue was dissolved in methanol (1 ml) and then sodium methoxide (0.2 ml; 0.5 N solution in methanol) was added. The mixture was heated to 120° C. for 10 minutes under microwave irradiation. Solvents were concentrated in vacuo and the residue was purified by HPLC using a C18 column with a gradient of H2O and 0.1% TFA-acetonitrile, to provide the pure title compound as a white solid (1 mg, yield: 2%) which was characterised by its mass spectrum as follows: MS (m/z) 269.0 [M+H]+; HPLC Rt=4.14 minutes (Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>ClCCl>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (319 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (117 μL, 1.40 mmol) and 4-tert-butylbenzoyl chloride (274 μL, 1.40 mmol) were added and the reaction was stirred at room temperature for 10 minutes. The crude mixture was absorbed onto silica and purified by column chromatography to give the title compound as an off-white solid (274 mg, 52% yield). MS (ES+) m/e=411. 1H NMR (CDCl3) δH 1.36 (12H, s), 1.39 (9H, s), 4.10 (3H, s), 7.55 (2H, d), 7.86 (2H, d), 8.28 (1H, s), 8.36 (1H, br s), 9.07 (1H, s).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[N:32]2)=[N:29][CH:30]=1.[Cl-].[Na+].Cl>C1COCC1.C([Li])CCC.O.CCOC(C)=O.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[F:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH:35]=[CH:34][C:33]([CH2:36][CH:2]=[O:3])=[N:32]2)=[N:29][CH:30]=1
Reactant: O=Cc1ccn(-c2ccc(F)cn2)n1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=CCc1ccn(-c2ccc(F)cn2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methoxymethyltriphenyl phosphonium chloride (5.4 g, 15.7 mmol) in THF (50 mL), n-butyl lithium (a 2.6 mol/L hexane solution, 6.3 mL, 16.5 mmol) was added under cooling at −78° C., and the resulting mixture was stirred for 30 minutes. The reaction mixture was heated to 0° C., a solution of 1-(5-fluoropyridin-2-yl)-1H-pyrazole-3-carbaldehyde obtained in Reference Example 29 (1.5 g, 7.9 mmol) and hexamethylphosphoric triamide (0.5 mL) in THF (50 mL) was added thereto, the resulting mixture was stirred for 3 hours, then heated to room temperature and stirred for 15 hours. To the reaction mixture, EtOAc and a saturated aqueous solution of sodium chloride were added under cooling in an ice bath and stirred to separate the organic layer. The organic layer was dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure to obtain a brown oil. To the obtained brown oil, an aqueous solution of hydrochloric acid (1.2 mol/L, 10 mL) was added, and the resulting mixture was heated to reflux and stirred for 2 hours. The reaction mixture was allowed to cool at room temperature, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HIP-Sil 25 g, hexane/EtOAc=80/20 to 20/80) to obtain the title compound (1.0 g) (light yellow oil).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:12]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][O:39][CH3:40])=[CH:33][C:32]=1[O:41][CH2:42][O:43][CH3:44])C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:44][O:43][CH2:42][O:41][C:32]1[CH:33]=[C:34]([O:37][CH2:38][O:39][CH3:40])[CH:35]=[CH:36][C:31]=1[C:12]1[N:11]([CH2:10][CH2:9][OH:8])[C:15]2=[N:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=[C:14]2[C:13]=1[CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCOCc3ccccc3)c2n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCOC)cc3OCOC)n(CCO)c2n1

Procedure:
To a solution of ethyl 1-(2-benzyloxyethyl)-2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (727 mg, 1.20 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 7.5% palladium carbon (225 mg), and the mixture was stirred at atmospheric pressure and in a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give ethyl 2-(2,4-bismethoxymethoxyphenyl)-3-cyclohexyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate as a crude product. The obtained compound was used in Step 7 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH:24][CH3:23])=[O:21])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCCc1cc(-c2ccc(Cl)cc2)no1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCCc1cc(-c2ccc(Cl)cc2)no1
Yield: 74.9 %

Procedure:
0.6 g (1.87 mmol) of 3-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}-1,3-oxazolidine-2,4-dione, prepared in stage 4.2., is dissolved in a mixture of 8 ml of tetrahydrofuran and of 15 ml of methanol. 2.8 ml of a 2M solution of methylamine (5.6 mmol) in tetrahydrofuran are added. Reaction is allowed to take place at ambient temperature overnight and then the mixture is evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a 98/2 and then 95/5 and 90/10 mixture of dichloromethane and of methanol. The product is recrystallized from a mixture of ethyl acetate and of methanol to produce 0.49 g (1.4 mmol) of white crystals.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:33])([O:26]C4CCCCO4)[CH3:25])[CH:15]=3)[CH:10]=[CH:11][C:4]=2[O:3]1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:6][C:5]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])([CH3:25])[CH3:33])[CH:15]=2)[CH:10]=[CH:11][C:4]=1[OH:3]
Reactant: CC(C)(CCCCc1cccc(C=Cc2ccc3c(c2)COC(C)(C)O3)c1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(O)CCCCc1cccc(C=Cc2ccc(O)c(CO)c2)c1

Procedure:
In a manner similar to Example 8(k), by reacting 313 mg (0.67 mmol) of 2,2-dimethyl-6-(2-{3-[5-methyl-5-(tetrahydropyran-2-yloxy)hexyl]phenyl}vinyl)-4H-benzo[1.3]dioxin in 10 ml of acetic acid, 5 ml of THF and 2.5 ml of water, and after purification on a silica column (ethyl acetate 40-heptane 60), white crystals (m=91 mg; Y=40%) are obtained. m.p.=130-1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(Cl)(=O)C(Cl)=O.[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[NH:30][CH2:29][C:28]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:24]1[CH:25]=[CH:26][N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH2:29][C:28]=12
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a suspension of 2,2′-dimethyl-biphenyl-4-carboxylic acid of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of a 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N,N-diisopropylethylamine (87 mL, 500 mmol). The reaction mixture stirred at room temperature under nitrogen for 16 hours. The mixture was then washed with 1 M hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g, 32%) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g, 30%) as a white solid, m.p. 145-148° C.