Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:46]1([CH2:52][O:53][NH2:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:35]2[N:36]=[C:37]([Cl:44])[N:38]=[C:39]([NH:54][O:53][CH2:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]=2[N:41]=[CH:42]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(NOCc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 43.4 %

Procedure:
(This example was also prepared by general method A). 9-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (0.77 g, 4.8 mmol) and diisopropylethylamine (1.03 g, 8.0 mmol) were dissolved in dioxan (50 ml). The reaction mixture was heated at reflux for 20 h, filtered and evaporated in vacuo. The crude product was coevaporated with dichloromethane and crystallised from a mixture of dichioromethane and methanol to provide the title compound (1.0 g, 43%), as white crystals, mp 115°-119° C., 1H NMR (CDCl3)γ 3.52-3.70 (2H, m, H-5'a and H-5'b) 3.95 (1H, d, H-4'), 4.15 (1H, dd, H-3'), 4.52 (1H, dd, H-2'), 5.00 (2H, s, CH2), 5.88 (1H, d, H-1'), 8.52 (1H, s, H-8).
Reaction SMILES: [C:1]1([CH:7](O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)[Cl:18]>C(Cl)Cl>[C:10]1([C:8](=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][Cl:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(c1ccccc1)C(O)c1ccccc1
Reactant: ClP(Cl)Cl
Solvent: ClCCl
Product: ClCC(=Cc1ccccc1)c1ccccc1

Procedure:
A solution comprised of 14 parts of 1,2-diphenyl-2-propen-1-ol and 24.3 parts of methylene chloride is added dropwise to a solution comprised of 12.6 parts of phosphorous trichloride and 30.4 parts of methylene chloride at a temperature of -15°. That reaction mixture is allowed to warm to 0° over a 3 hour period. Then ice is added while stirring rapidly and the oil which separates is extracted with ethyl ether. The ethereal extracts are washed with water and then with 10% potassium bicarbonate solution. After drying over anhydrous sodium sulfate, the solution is reduced to an oil by evaporating the solvent under a nitrogen stream and reduced pressure to yield pure 2,3-diphenylallyl chloride.
Reaction SMILES: [O:1]1[C:6]2([CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][S:4][C:3]2[C:13](=[O:22])[C:14](=[O:21])[C:15]3[C:20]([C:2]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:9]1[CH2:10][CH2:11][CH2:12][C:6]2([O:1][C:2]3[C:20]4[C:15]([C:14](=[O:21])[C:13](=[O:22])[C:3]=3[S:4][CH2:5]2)=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:7][CH2:8]1)=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 62 was synthesized using spiro[azepane-4,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=98-100° C., 400 MHz 1H NMR (CDCl3) δ: 8.08-8.06 (m, 1H), 7.76-7.66 (m, 2H), 7.52-7.48 (m, 1H), 7.42-7.21 (m, 4H), 3.87-3.86 (m, 1H), 3.67-3.49 (m, 3H), 3.05-2.92 (m, 2H), 2.39-2.17 (m, 4H), 2.04-1.96 (m, 1H), 1.89-1.76 (m, 1H); LCMS: 454 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=2)[C:20]([Cl:19])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(NCc2cc(F)c(F)c(F)c2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N(Cc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 124.5 %

Procedure:
To a solution of 3.4 g (13.30 mmol) of 3-fluorophenyl-(3,4,5-trifluorobenzyl)amine (Intermediate I-8) in 25 ml of methylene chloride, cooled at −10° C., was added slowly with stirring a solution of 2.0 g (6.70 mmol) of triphosgene in 15 ml of methylene chloride. The reaction was allowed to warm to room temperature and stirred for 17 hours at this temperature. After this time the solid formed during the process was filtered and the filtrate was concentrated in vacuo. The obtained residue was treated with n-hexane at −25° C. The soluble part was separated and filtrated. The filtrate was concentrated in vacuo to dryness to give 2.65 g (62.8%) of the tide product as an oil. The structure was confirmed by 1H-NMR.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc([N+](=O)[O-])cc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-ethylaniline (12.1 g, 99.8 mmol, 1 equiv) was dissolved in concentrated sulphuric acid (50 ml) and cooled down to 0° C. Fuming nitric acid (9.3 g, 147.6 mmol, 1.5 equiv) was then added slowly keeping the temperature below 5° C. The reaction was left warm up to room temperature and stirred overnight. The reaction mixture was poured onto ice-water (250 ml) and neutralised with sodium hydroxide 6M. The solid was filtered off and dried in an oven to remove as much water as possible. The red solid was then taken up in petrol (250 ml×4) and decanted over filter paper to crystallise out the desired compound as yellow solid. (2.7 g, 17%). 1H NMR spectra were recorded at ambient temperature using a Bruker Advance DRX (400 MHz) spectrometer, both with a triple resonance 5 mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:39].[C:40]1([P:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CC(C)=O>[I-:39].[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][P+:46]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12

Procedure:
32.5 g (0.0609 mol) of benzhydryl 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate are dissolved in 330 ml of acetone, and 10.1 g (0.0674 mol) of NaI and 17.6 g (0.0671 mol) of triphenylphosphine are added in succession, with stirring. After the mixture has been stirred at room temperature for 1.5 hours, the insoluble material is removed by filtration with suction and the clear mother liquor is stirred into 1,000 ml of ether. The white flocculent material which precipitates out is filtered off with suction, washed with 300 ml of ether and dried in vacuo.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.C(O)(C(F)(F)F)=O.[NH2:27][C@H:28]([C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([NH2:42])=[O:41])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CN(C=O)C.COCCOC>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:27][C@H:28]([C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([NH2:42])=[O:41])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
44 g Boc-Gly-OH (1 equivalent) was dissolved in a mixture of 50 ml DMF and 300 ml DME and subsequently cooled to −15° C. 28 ml NMM (1 equivalent) was added at once, followed by the dropwise addition of 34 ml IBCF (1 equivalent) over 10 min. The mixture was stirred a further 5 min at −15° C. 94.5 g TFA.H-L-Phe-L-Pro-NH2 (1.06 equivalents) were added in portions thereto over 5 min, followed by the addition of 44 ml DIEA (1 equivalent). The reaction mixture was reacted over night at room temperature and atmospheric pressure. Subsequently, the reaction mixture was concentrated in a rotatory evaporator, equipped with a water aspirator and a dry ice/acetone trap, and the residue was taken in 1.2 l ethyl acetate, followed by five washes with 80 ml 1N aqueous KHSO4 solution, five washes with 80 ml saturated aqueous NaHCO3 solution, and one wash with 80 ml brine in a 2 l separatory funnel. The subsequent drying was carried out over 50 g Na2SO4. After filtration through a sinter glass funnel (coarse porosity) concentration was carried out as described above. The residue of evaporation (sticky oil) was then triturated in a mixture of 1 l diethyl ether and 2 l hexane and a solid was collected on a sinter glass funnel (180 mm i.d.×180 mm, medium porosity). The subsequent drying was carried out in a desiccator over 12 hours at room temperature and a pressure of 0.1 to 1 mm Hg (vacuum oil pump, with dry ice/acetone trap). Accordingly, 100 g Boc-Gly-L-Phe-L-Pro-NH2 was obtained (yield: 94.7%).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[OH:29][C@H:16]1[CH2:15][CH2:14][C@@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20][C@:21]3([CH3:26])[C@@H:12]2[CH2:11][CH2:10][C@H:9]2[C@@:22]3([CH3:25])[CH2:23][CH2:24][C@@:7]3([C:31]([O:33][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:32])[CH2:6][CH2:5][C@@H:4]([C:2]([CH3:1])=[CH2:3])[C@@H:8]32)[C:17]1([CH3:27])[CH3:28]
Reactant: BrCc1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 97 %

Procedure:
To a suspension of betulinic acid (12 g, 26.3 mmol) and potassium carbonate (7.26 g, 52.6 mmol) in DMF (150 mL) was added benzyl bromide (3.28 mL, 27.6 mmol). The mixture was heated to 60° C. for 3.5 h, and then it was cooled to rt. Solids started to precipitate upon cooling. The mixture was diluted water (200 mL) and the solids that formed were collected by filtration to give the title compound (13.92 g, 25.5 mmol, 97% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.39-7.28 (m, 5H), 5.16-5.06 (m, 2H), 4.71 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.17 (ddd, J=11.44, 5.65, 5.49 Hz, 1H), 3.01 (td, J=10.99, 4.88 Hz, 1H), 2.27 (ddd, J=12.36, 3.20, 3.05 Hz, 1H), 2.21-2.13 (m, 1H), 1.93-1.81 (m, 2H), 1.67 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 1.71-0.82 (m, 20H), 0.79 (s, 3H), 0.75 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:28]=[CH:27][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:62]1([C@H:68]([NH2:70])[CH3:69])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:21][CH2:22][CH2:23][C:24]([NH:70][C@@H:68]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH3:69])=[O:25])=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.6 %

Procedure:
To a suspension of 4-{(S)-2-[4-(4-chloro-phenyoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid HCl salt (220 mg, 0.5 mmol, 1 eq.) in dichloromethane (5 ml) was added PyBrOP (280 mg, 0.6 mmol, 1.2 eq.), DIPEA (200 mg, 1.5 mmol, 3 eq.) and (R)-1-phenyl ethylamine (80 mg, 0.6 mmol 1.2 eq.). The mixture was stirred at room temperature for 24 h. The mixture was poured onto 30 mL ice-water solution and this solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to provide the crude product which was purified by silica gel flash chromatography to afford the title product (68 mg, 25%); LCMS; 95%; APCI+, Calcd 493.05. Found m/z 493.2 (M). 1H NMR (400 MHz, CDCL3); δ 1.47 (d, J=5.6 Hz, 3H), 1.52-2.01 (m, 6H), 2.21-2.59 (m, 4H), 2.79-2.98 (m, 2H), 3.12-3.23 (m, 1H), 3.68-3.89 (m, 2H), 5.10-5.17 (m, 1H), 6.81 (d, J=9.2 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 7.22-7.26 (m, 5H), 7.29 (d, J=4.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[CH:4][CH:3]=1.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH:24]([OH:25])[C:30]([F:33])([F:32])[F:31])=[CH:4][CH:3]=1
Reactant: CCC(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(O)C(F)(F)F
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butanal (51.8 mg, 0.123 mmol) and trimethyl(trifluoromethyl)silane (54.3 μL, 0.368 mmol) in tetrahydrofuran (0.6 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 12.3 μL, 0.0123 mmol) at 0° C. After 30 min, hydrochloric acid (1.0 M, 0.25 mL) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (49.0 mg, 0.0995 mmol, 81%).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]([NH2:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)[CH2:8][CH2:7]1)(OCC)=[O:2].[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[O:29]1[CH:30]=[CH:31][CH:28]=[C:27]1[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:21]=[C:20]([NH2:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)[CH2:10][CH2:11]1)=[O:2]
Reactant: CCOCC
Reactant: CCOC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To the above mixture is added slowly at -20° C., 32.9 g. (0.10 mole) of 2-(4-carbethoxypiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline dissolved in 300 ml. of ethyl ether. The reaction mixture is stirred at -20° C. for 2 hours, then allowed to warm to room temperature. The resulting mixture is hydrolyzed by addition of 100 ml. of water, and the ether layer separated. The aqueous layer is extracted with 300 ml. of ether and the combined extracts are dried over anhydrous magnesium sulfate. Evaporation of solvent affords 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline which can be further pruified if desired by silica gel column chromatography.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][C@@H:3]1[NH:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)[N:20]=1.Cl.O>CO>[F:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[NH:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)[N:20]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](F)[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: F[C@@H]1CCNC[C@@H]1Nc1cncc(-c2cnn3ccccc23)n1
Temperature: 100 °C
Yield: 96 %

Procedure:
Benzyl (3s,4r)-4-fluoro-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]piperidine-1-carboxylate (Preparation 41a, 229 mg, 0.51 mmol) was added to a 3N hydrochloric acid solution in methanol (45 mL) and the resulting mixture was heated overnight at 100° C. in a sealed tube. A 37% aqueous hydrochloric acid solution (10 mL) was then added and the reaction mixture was stirred at 100° C. for four additional hours. After cooling to ambient temperature, water was added and the organic solvent was evaporated under reduced pressure. The resulting aqueous phase was washed with methylene chloride, basified by addition of an aqueous 2N sodium hydroxide solution until a basic pH was reached and washed again with methylene chloride (×3). The combined organic phases were washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo to yield the title compound (153 mg, 95%) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.Br[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynyl chroman (from Example 10) in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 4-bromobenzoate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and stirred at room temperature for 15 minutes, then treated by double ended needle with the solution of alkynyl zinc chloride prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was then extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to obtain the captioned compound as a white solid. PMR (CDCl3): δ 1.36 (6H), 1.42 (3H, t, J~7.3 Hz), 1.82-1.86 (2H, m), 4.21-4.25 (2H, m), 4.40 (2H, q, J~7.3 Hz), 6.79 (1H, d, J~8.1 Hz), 7.28 (1H, dd, J~8.1 Hz, 2.2 Hz), 7.50 (1H, d, J~2.2 Hz), 7.58 (2H, d, J~8.7 Hz), 8.03 (2H, d, J~8.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[O:31]1[C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:36]([C:35]5[O:31][N:32]=[CH:33][CH:34]=5)=[O:37])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Reactant: O=C(O)c1ccno1
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccno3)CC2)n1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with isoxazole-5-carboxylic acid to yield the title compound as light yellow solid. MS: 523.1 (MH+, 1Cl).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>>[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:32])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: Nc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(N)c(C(F)(F)F)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-amino-3-(trifluoromethyl)benzoic acid as starting compounds. The crude product is purified by column chromatography (silica gel and DCM/methanol=4:1) and crystallization from methanol to yield the title compound.