Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([O:23][C:24](=[O:33])[C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].CO>[C:17]1([CH2:16][CH:15]([O:23][C:24](=[O:33])[C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](C(=O)OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@H](C(=O)OC(Cc1ccccc1)CC1CCNCC1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 0.310 g (0.7 mmol) of 1-benzyl-4-(3-phenyl-2-((S)-2-phenylpropionyl)oxypropyl)piperidine (Step 1a, isomer 1a), 0.8 g of ammonium formate, and 0.3 g of Pearlman's Catalyst (Pd(OH)2, 20% Pd, moist, Degussa type) in 20 mL of methanol was heated at reflux for 1 h. The mixture was cooled to rt and filtered through a pad of celite and concentrated to afford isomer 1b of the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:75][NH:76][O:77][CH3:78]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:76]([O:77][CH3:78])[CH3:75])[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1-trityl-1H-imidazol-4-yl)-propionic acid (4.56 g, 9.18 mmol), DIPEA (3.55 g, 4.79 mL, 27.53 mmol), BOP (4.26 g, 9.63 mmol) and N,O-dimethylhydroxylamine hydrochloride (940 mg, 9.63 mmol) in DMF (100 mL) were stirred overnight. The DMF was removed and CH2Cl2 added. The solution was washed with dilute aqueous HCl (1M, 4X), water and brine. The solution was dried, filtered and the solvent removed. The product was chromatographed (silica gel, EA/PE, Rf 0.38 EA) to afford the title compound (4.475 g, 90.4%). ESMS 541 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.92 (1H, dd, J=6.13, 14.45), 2.98 (1H, dd, J=5.63, 14.45), 3.13 (3H, s), 3.73 (3H, s), 4.87 (1H, m), 5.61 (1H, d, J=6.95 Hz), 6.57 (1H, s), 7.11 (6H, m), 7.32 (9H, m), 7.46 (1H, s). 13C NMR (CDCl3) 28.19, 30.34, 31.02, 50.55, 61.49, 75.62, 79.34, 119.74, 127.98, 129.59, 135.19, 137.95, 141.77, 155.19, 171.77.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[O:11][CH2:12][CH2:13][C:14]3([CH2:16][CH2:15]3)[C:6]=12.Cl.O>CO>[C:14]12([C:6]3[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][C:7]=3[O:11][CH2:12][CH2:13]1)[CH2:16][CH2:15]2
Reactant: COCOc1cccc2c1C1(CCO2)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc2c1C1(CCO2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
5-{[(methyloxy)methyl]oxy}-2,3-dihydrospiro[chromene-4,1′-cyclopropane] (Intermediate 220, 145 mg, 0.658 mmol) was dissolved in MeOH (6.0 mL) and a 2N aqueous solution of HCl (0.494 mL, 0.99 mmol) was added and the reaction mixture was stirred at 50° C. overnight. After addition of water, MeOH was removed under vacuum and the aqueous phase was extracted with ethyl acetate (three times). Combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound (64 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][C:5]1([CH3:17])[CH3:16].[C:18]([N:22]=[C:23]=[O:24])([CH3:21])([CH3:20])[CH3:19].O.C(OCC)(=O)C>C1COCC1>[C:18]([NH:22][C:23](=[O:24])[NH:1][CH2:2]/[CH:3]=[C:4]1/[C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][C:8]2[C:13]/1=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc2c(c1)C(=CCN)C(C)(C)CC2
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)/C(=C\CNC(=O)NC(C)(C)C)C(C)(C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-aminoethylidene)-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene (1.5 g, 6.48 mmol) in THF (30 ml) was gradually added dropwise, under ice-cooling, Tert-butyl isocyanate (0.84 g, 8.43 mmol). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then poured into water. The organic layer was subjected to ethyl acetate. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=8:2),-followed by recrystallization to give the above-titled compound (yield 780 mg, 36%), m.p.175-176° C. (recrystallized from ethyl acetate/diethyl ether).
Reaction SMILES: S(C)C.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]=[C:8]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>C1COCC1>[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([OH:14])[CH:9]=[C:8]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=CC2=O
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1ccc2c(c1)C(c1ccccc1)=C[C@@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
(R)-MeCBS catalyst (0.22 ml, 1 M, 0.22 mmol) was mixed in 5 ml of dry THF, and stirred for 1 h at room temperature. After cooling to 0° C., 2.5 ml of 2 M BH3:Me2S (4.99 mmol) in THF were added. 5-Methyl-3-phenyl-inden-1-one (1.00 g, 4.54 mmol) was added as a solution in toulene (2 ml) over 2 h via a syringe pump. The reaction was followed by TLC. After completeness, methanol (0.6 ml, 17 mmol) was added at 0° C. and the mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 0.96 g (95%) of the title compound. Rf 0.35 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 24.53 min, (R)-isomer 27.22 min, 93% ee. IR (neat cm−1): 3300, 1605, 1446, 949, 813. 1H NMR δ: 1.40 (s, 1H), 2.40 (s, 3H), 5.27 (d, J=8 Hz, 1H), 6.43 (d J=2 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.27 (s, 1H), 7.47 (m, 4H), 7.59 (m, 2H). 13C NMR δ: 21.6, 76.2, 121.6, 123.6, 126.9, 127.6, 128.2, 128.6, 134.1, 134.9, 138.2, 142.1, 143.7, 145.6. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (71), 178 (66), 144 (42), 116 (23).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:27][CH3:28])[C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH:8]=[O:9].CO.O>O1CCCC1>[CH3:28][O:27][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:8][OH:9]
Reactant: COc1cc(C=O)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CO)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium borohydride (540 mg) was added to a solution of 3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (10.0 g) in tetrahydrofuran (70 ml)-methanol (30 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water to give 3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (9.25 g, yield 92%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms. m.p. 113-114° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]([CH2:12][CH2:13][O:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:19][S:16]([CH2:15][O:14][CH2:13][CH2:12][N:9]1[C:8]2[CH:20]=[CH:21][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1)(=[O:17])=[O:18]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCOCS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)COCCn1cnc2cc(C(=O)O)ccc21
Reaction time: 1 h
Yield: 83.8 %

Procedure:
1-(2-Methanesulfonylmethoxyethyl)-1-H-benzimidazole-5-carboxylic acid methyl ester (1.0 g, 3.2 mmoles) was dissolved in THF (5 mL). A solution of LiOH (0.38 g, 16 mmol) in water was added and the mixture stirred vigorously for 1 h. The reaction was acidified with 2N HCl to pH 2 at 5-10° C. It was then filtered to give 0.8 g (84%) of 1-(2-methanesulfonylmethoxyethyl)-1H-benzoimidazole-5-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 2.9 (s, 3H), 4.2 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.75 (d, 1H), 7.9 (dd, 1H), 8.25 (d, 1H), 8.35 (s, 1H), 12.7 (s, 1H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]([F:37])=[C:9]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH3:28])[N:20]=3)=[CH:17][N:16]([CH:34]([CH3:36])[CH3:35])[N:15]=2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:13][C:11]1[CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]([F:37])=[C:9]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH3:28])[N:20]=3)=[CH:17][N:16]([CH:34]([CH3:35])[CH3:36])[N:15]=2)[CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(Cl)cc(N)c2F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2-c2cc(Cl)cc(NS(C)(=O)=O)c2F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (0.277 mL, 3.57 mmol) was added to a solution of (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (550 mg, 1.2 mmol) in DCM (30 mL) and pyridine (10 mL), and the mixture was stirred at rt for 16 h. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (60:1 to 40:1 DCM/methanol) to provide the title compound. An alternative synthesis is described in example 6, infra.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:9][CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:8]1[N:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(-c2cccs2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc(-c2cccs2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.175 g of 2-thiophen-2-yl-pyrimidine-5-carboxylic acid methyl ester was dissolved in 3 mL of tetrahydrofuran. The reaction was cooled to 0° C. (ice-water bath) and then 2.39 mL of diisobutylaluminumhydride (1.0 M in tetrahydrofuran) were added dropwise. The reaction was left stirring at 0° C. for 30 minutes, then at room temperature overnight. Water was added, the mixture was extracted with ethylacetate, and the organic layer was dried with magnesium sulphate, filtered and concentrated to afford the crude (2-thiophen-2-yl-pyrimidin-5-yl)-methanol, which was used without purification for the next reactions.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31](=[O:33])[CH3:32])=[CH:29][N:30]=2)[N:27]=1>C1COCC1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:12])[N:7]=[CH:6][CH:5]=[CH:4]4)([OH:33])[CH3:32])=[CH:29][N:30]=2)[N:27]=1
Reactant: Fc1cc(F)c2cccnc2c1
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reaction time: 1 h

Procedure:
A solution of 5,7-difluoro-quinoline (CAS 34522-72-0, 18.57 g, 112 mmol) in dry THF (120 mL) was added dropwise to a freshly prepared solution of LDA (n-BuLi 77 mL and diisopropylamine 18.94 mL, 123 mmol, in 500 mL THF) at −78° C. The solution was stirred at this temperature for 1 h, and then the solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)ethanone (CAS 90734-71-7, 20.0 g, 102 mmol) in 400 mL THF was added dropwise at −70° C. After stirring additional 45 min at −70 to −30° C. the RM was quenched with 1M NH4Cl, diluted with water, and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and then crystallized in DCM to afford the title compound as a beige solid (tR 2.94 min (conditions 1), MH+=361, 1H-NMR in DMSO-d6: 8.93 (d, 1H); 8.43 (d, 1H); 8.18 (d, 1H); 7.92 (s, 1H); 7.57 (m, 2H); 7.24 (d, 1H); 6.49 (s, 1H); 2.18 (s, 3H)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1>CO>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1cccc(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1cccc(F)c1)OC
Yield: 53 %

Procedure:
N-(3-Fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (53% yield); mp 73–75° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.71 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.82 (2H, s, NCH2), 6.47 (1H, s, CH), 6.98–7.34 (4H, m, aromatics). Anal. calcd for C13H14FNO5: C, 55.12; H, 4.98; N, 4.94. Found: C, 55.18; H, 5.04; N, 5.02.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccnc1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccnc1
Yield: 55.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 427 mg of 3-aminopyridine in place of the 2,4-difluoroaniline. 168 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(pyridin-3-yl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.OC1C=CC=CC=1>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Reaction time: 20 h

Procedure:
A 2 l three-neck flask equipped with a mechanical stirrer was charged with 42.4 g (0.2 mol) of 4-hydroxy-4′-methylazobenzene synthesized in the same manner as in the Example, 448 g (2 mol) of 1,6-dibromohexane and 212 g (1.5 mol) of potassium carbonate anhydride. To the mixture was added 800 ml of acetone and the resulting mixture was suspended by stirring. The reaction system was heated until acetone was refluxed to react hydroxybenzene with bromoalkane. After the reaction was continued for 20 hours, insoluble salts were separated by filtration and removed. The system was concentrated to a volume of about ⅓ by using a rotary evaporator. When the system was cooled in a freezing chamber, 4-(6-bromohexyloxy)-4′-methylazobenzene was produced as a crystal. After the generated product was subjected to filtration, it was washed with a small amount of cool acetone, cool ether and n-hexane in this order and then dried under reduced pressure to obtain 38.1 g of crude 4-(6-bromohexyloxy)-4′-methylazobenzene (yield: 50.8%). The resulting product was recrystallized from ethanol to obtain 32 g (yield: 42%) of 4-(6-bromohexyloxy)-4′-methylazobenzene. It was found from an analysis using high performance liquid chromatography that the purity of the product was 98.6% or more.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:23](O)=[O:24])[C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:15][NH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C:26]([O:28][CH3:29])=[O:27].[CH2:30]([NH2:45])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH2:44]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:11]3=[C:10]([C:23](=[O:24])[NH:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:45][C:23]([C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:26]([O:28][CH3:29])=[O:27])[CH:4]=4)[N:13]=[C:12]4[NH:14][N:15]=[C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:11]=34)=[O:24])[CH:9]=2)=[CH:4][C:3]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: NCCOCCOCCOCCOCCN
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccccc4)n[nH]c3n2)ccc1F
Product: COC(=O)c1cc(-c2cc(C(=O)NCCOCCOCCOCCOCCNC(=O)c3cc(-c4ccc(F)c(C(=O)OC)c4)nc4[nH]nc(-c5ccccc5)c34)c3c(-c4ccccc4)n[nH]c3n2)ccc1F
Yield: 66 %

Procedure:
Obtained according to the process described in Step 1.10, using 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid [described in Step 1.9.] and 3,6,9,12-tetraoxatetradecane-1,14-diamine, in the form of a white powder (yield: 66%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:29])[C@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].OS([O-])(=O)=O.[K+].[CH2:37]([O:39]CC)C>>[C:16]([O:15][C:13]([NH:12][C@H:11]([CH:10]=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][O:39][CH3:37])=[CH:25][CH:26]=1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOCC
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC)cc1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Product: COOc1ccc(C[C@@H](C=O)NC(=O)OC(C)(C)C)cc1
Temperature: 4 °C

Procedure:
To 150 ml of anhydrous ethyl ether was added 1.04 g (27.37) mmols) of lithium aluminum hydride and the suspension was gently refluxed for 30 minutes. Upon cooling to 4° C., the reflux condenser was replaced by a pressure equalizing dropping funnel containing 7.4 g (21.9 mmols) of N-(t-butoxycarbonyl)-O-methyl-L-tyrosine N-methoxy-N-methylamide dissolved in 100 ml of anhydrous ethyl ether. The contents of the funnel were added over one hour. The reaction mix was allowed to react for an additional two hours. At the end of this time a cold solution of KHSO4 (5.433 g in 230 ml of H2O) was added to the reaction vessel. The layers were separated and the aqueous layer was extracted three times with 150 mls of ether each time. The ether layers were combined and worked up as follows. Washed three times with 200 mls of 3N HCl. Washed three times with 200 mls of saturated sodium bicarbonate. Washed three times with 200 mls of brine. Dried over magnesium sulfate, filtered, and concentrated in vacuo. There remained 3.78 g (61.6%) of a white solid with a mp of 69°-72° C.: Rf=0.65 in 50/50 ethyl acetate/hexane; IR (cm-1, KBr) 3360, 2840, 1740, 1695, 1530, 1255, 1180: MS m/e 279.3 (M+); 1 H (CDCl3), 300 MHz) δ9.63 (s, 1H), δ7.08 (d, 2H, J=8.5 Hz) δ6.84 (d, 2H, J=8.5), δ5.05 (br s, 1H), δ4.40 (m, 1H), δ3.79 (s, 3H), δ3.06 (d, 2H, J=6.50), δ1.44 (s, 9H); 13C NMR (CDCl3, 75.47 MHz) δ200, 158.79, 130.28, 127.69, 114.27, 61.05, 55.29, 34.70, 28.26; Anal. Calcd: C, 64.51; H, 7.52; N, 5.01. Found: C,64.60, H, 7.86; N, 4.93.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH2:16]C)=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>OS(O)(=O)=O.CO>[C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1ccc(-c2ccc(C(=O)OCC)nc2-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCc1ccc(-c2ccc(C(=O)OC)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure E, ethyl 6-phenyl-5-(4-propylphenyl)-pyridine-2-carboxylate (Compound 24, 67 mg, 0.19 mmol) and conc. H2SO4 (3 drops) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:13](=O)(OC(C)(C)C)OC(C)(C)C.[Cl-].[NH4+].C(=O)([O-])N.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl.C1COCC1>[CH3:13][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: NC(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
A mixture of 4-(trifluoromethyl)benzylamine (1.0 mL, 7.02 mmol) and di-tert-butyl carbonate (1.68 g, 7.72 mmol) in CH2Cl2 (10 mL) was stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution, extracted with CH2Cl2 and the organic layers were combined, dried over MgSO4 and concentrated in vacuo to give a white crystalline solid. To a solution of the crude carbamate (1.00 g, 3.61 mmol) in THF (20 mL) in a room temperature water bath, was added LiAlH4 (0.69 g, 18.1 mmol) portion-wise over 10 minutes. The reaction was then heated at reflux for 4 hours. The reaction was cooled in ice and quenched by the addition of water (1.6 mL) and NaOH (2N, 1.3 mL). The grey slurry was filtered and washed with MeOH. The MeOH was removed in vacuo and the crude product taken up in CH2Cl2 and dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography eluting with 5-10% MeOH in CH2Cl2 plus 1% NH3 solution (2N in MeOH) afforded the title compound.