Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[CH:3][CH:4]=1)[CH3:15]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate, intermediate 9, (100 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylboronic acid (57.6 mg, 0.34 mmol) in toluene (1 mL) and EtOH (0.1 mL) is added Pd(PPh3)4 (26.1 mg, 0.023 mmol) and Na2CO3 (47.9 mg, 0.45 mmol). After stirring at 95° C. under nitrogen for 18 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The crude is diluted with ethyl acetate, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 30:70) to give (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate (65 mg). HPLC retention time=1.44 minutes (condition B); MS (m+1)=488.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.1 Hz, 3H) 1.48 (s, 9H) 2.41-2.48 (m, 2H) 2.51-2.63 (m, 4H) 2.90 (dd, J=13.6, 6 Hz, 1H) 3.02 (dd, J=13.6, 6 Hz, 1H) 3.81 (s, 3H) 4.14-4.29 (m, 2H) 4.49-4.63 (m, 1H) 6.44 (d, J=8.6 Hz, 1H) 6.89-6.97 (m, 1H) 6.98-7.05 (m, 1H) 7.05-7.11 (m, 1H) 7.27 (d, J=8.1 Hz, 2H) 7.49 (d, J=8.1 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:12][C@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A mixture of 4-nitrobenzaldehyde (30.22 g, 0.2 mol), 1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (40.06 g, 0.2 mol) and sodium tri(acetoxy)borohydride (85 g, 0.4 mol) in 1,2-DCE (1 L) was stirred at room temperature over-weekend. The reaction mixture was treated portion-wise with NaHCO3 solution (400 mL) over a period of ˜2 h. After a further 30 minutes, the organic layer was separated, washed with brine, dried and concentrated to give a viscous pale yellow oil. Purification by column chromatography eluting with 0%, 10% and then 20% EtOAc/hexane yielded the title compound as a yellow crystalline solid (61.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[C:6](=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:7]=O.[CH3:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][S:21]([CH2:24][C:25]([OH:27])=[O:26])(=[O:23])=[O:22])=[CH:18][CH:17]=1>C(O)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][S:21]([C:24]2[C:25](=[O:27])[O:26][C:5]3[C:6]([CH:7]=2)=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:22])=[O:23])=[CH:28][CH:29]=1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3c(OC)cc(OC)cc3oc2=O)cc1
Yield: 58 %

Procedure:
A solution of 4,6-dimethoxysalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 58% yield of the title compound; m.p. 183-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:15])[C:13]=1F)[C:5]([O:7][CH2:8][C:9]#[CH:10])=[O:6].[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C=O)C>[F:15][C:12]1[CH:11]=[C:4]([CH:3]=[C:2]([F:1])[C:13]=1[O:19][CH2:16][C:17]#[CH:18])[C:5]([O:7][CH2:8][C:9]#[CH:10])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(F)c(F)c1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(F)c(OCC#C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of 5.0 g of 2-propynyl 3,4,5-trifluorobenzoate and 1.7 g of propargyl alcohol in 20 ml of DMF was added 1.1 g of 60% sodium hydride (oily) at 0° C. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.9 g of 2-propynyl 3,5-difluoro-4-(2-propynyloxy)benzoate represented by the formula:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].C1(=O)O[CH2:18][CH2:17][O:16]1.[I-].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:16][CH2:17][CH2:18][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14]
Reactant: O=C1OCCO1
Reactant: Oc1ccccc1-c1ccccc1O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCOc1ccccc1-c1ccccc1O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
To a 2000 ml 3 neck round bottom equipped with an overhead stirrer, temperature probe, heating mantel was added 2,2′-dihydroxy-biphenyl (500 g, 2.68 mole, 1.0 eq), ethylene carbonate (520.2 g, 5.9 mole, 2.2 eq.), potassium iodide (5 g, 0.03 mole, 0.01 eq.), N,N-dimethyl formamide (DMF) (47 g, 50 ml) and heated to 150° C. The reaction was monitored by GC and after 4 hours the reaction was complete. The reaction was cooled to 40° C., added 1000 ml ethyl acetate and washed 3 times with 500 ml sodium chloride brine. The ethyl acetate was dried over MgSO4, filtered and concentrated in vacuo to recover a dark brown product (736 g, 99%).
Reaction SMILES: CO[CH:3]([CH3:11])[C:4](OC)(OC)OC.[F:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[C:26]3[N:25]=[C:24]([NH:27][NH2:28])[NH:23][C:22]=3[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:19]=2)=[CH:15][CH:14]=1>C(O)C>[F:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[C:26]3[N:25]=[C:24]([N:27]4[CH:11]=[CH:3][CH:4]=[N:28]4)[NH:23][C:22]=3[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:19]=2)=[CH:15][CH:14]=1
Reactant: NNc1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Reactant: COC(C)C(OC)(OC)OC
Solvent: CCO
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-n4cccn4)nc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.012 ml of tetramethoxypropane was added to an ethanol (0.3 ml) solution of 8.3 mg of (4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-1H-benzimidazol-2-yl)-hydrazine, and the reaction liquid was stirred overnight at 80° C. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[O:16]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)=[CH:12][O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: CC(=O)Oc1ccc(C2=COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc(C2=COc3ccccc3O2)cc1
Yield: 77.4 %

Procedure:
A mixture of 4-(benzo[b][1,4]dioxin-2-yl)phenyl acetate (270 mg, 1.0 mmol) in MeOH:THF (5 mL:3 mL) and K2CO3 (167 mg, 1.2 mmol) was stirred for 30 min at rt. The solvent was removed under reduced pressure and water was added. The solution was neutralized by dilute HCl and the solid was isolated by filtration, washed well with water and dried to give 175 mg of 4-(benzo[b][1,4]dioxin-2-yl)phenol (77%). MS (ES) m/z: 225.97 (M), 224.93 (M−1); Mp. 137-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]\[CH:11]=O)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:11]/[CH:10]=[C:9](\[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(/C(=C\C=O)c2ccccc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(/c1ccccc1)c1ccc(OC)cc1
Yield: 71 %

Procedure:
As described in Example 99, (Z)-3-(4-methoxyphenyl)-3-phenyl-2-propenal (7.3 g) was treated with (carbomethoxymethylene)triphenylphosphorane (11.9 g) in carbon tetrachloride (50 mL) and dichloromethane (10 mL) overnight at room temperature. The crude ester was isolated in the usual way and purified by HPLC (ether-hexane; 1:7.5) to furnish 6.4 g of (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1.[H-].[Na+].[CH:25]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1OC
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Reaction time: 1 h
Yield: 46.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-(3,4-dimethoxy-benzyl)-amine (799 mg, 2.5 mmol) was dissolved in dry DMF (10 mL). NaH (78 mg, 3.25 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (633 mg, 4.25 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (451 mg, 46.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.27.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NN2CCN(C)CC2)s1
Solvent: O
Solvent: CCO
Product: CN1CCN(NC(=O)c2ccc(C(=O)NN)s2)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
Methyl 5-(4-methylpiperazin-1-ylcarbamoyl)thiophene-2-carboxylate (218 mg, 0.77 mmol) in ethanol (60 mL) was refluexed with heating with hydrazine monohydrate (0.40 mL) for 6 hours and allowed to cool to room temperature, and the solvent was evaporated at 40° C. mL of diethyl ether was added to the resulting oil, and the precipitated solid was collected by filtration, washed with water and dried to give 142 mg of the desired product (yield 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:24])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:24])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A 1000 mL 3-necked round-bottom flask was charged with bis(4-chlorophenyl)methanol (49.6 g, 196 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), dichloromethane (100 mL). Liquid thionyl chloride (93.3 g, 790 mmol, 4.00 equiv) was added dropwise. The resulting solution was stirred overnight at 40° C. in an oil bath. The resulting mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/5) to provide 47.8 g (88% yield) of 1-chloro-4-[chloro(4-chlorophenyl)methyl]benzene as a gray solid. 1HNMR 300 MHz (CDCl3) δ 7.30-7.39 (m, 8H), 6.07 (s, 1H). GCMS (EI, m/z): 270 [M]+.
Reaction SMILES: O.[C:2]([C:10]([OH:12])=[O:11])(=[O:9])C1C=CC=CC=1.[CH2:13](O)[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([O:12][CH2:16][CH2:15][CH:14]=[CH2:13])(=[O:11])[CH:2]=[O:9]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: C=CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCCOC(=O)C=O
Temperature: 110 °C
Yield: 85.9 %

Procedure:
In a flask with a water separator, a mixture of 11.02 g of benzoylformic acid (glyoxalic acid), 6.62 g of 3-buten-1-ol and 0.42 g of p-toluenesulfonic acid in 130 ml of toluene is heated at 110° C. for 22 hours. The solution is washed with saturated NaHCO3 solution and water. The organic phases are dried over sodium sulfate. Filtration, evaporation of the solvent and distillation (b.p.=85° C. at 0.035 mbar) give but-3-enyl glyoxalate (8.08 g, 54%) as a pale yellowish liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3](=[O:23])[CH:4](NC(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[ClH:25]>O1CCOCC1>[ClH:25].[CH3:24][N:2]([CH3:1])[C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:12])[F:14])[CH:6]=1
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
130 mg (375 μmol) of the compound from Example 174A are stirred at RT in 2 ml of a 4 M solution of hydrogen chloride in dioxan. After complete conversion, the volatile components are removed on the rotary evaporator and the residue dried under high vacuum. 105 mg (99% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]2=[N:7][CH:8]=1.CC[C:24]([O-:26])=[O:25].[OH-].[Na+]>C(O)C>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:24]([OH:26])=[O:25])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]2=[N:7][CH:8]=1
Reactant: CCC(=O)[O-]
Reactant: Fc1cccc(Cn2ccc3cc(C(F)(F)F)cnc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 99.7 %

Procedure:
A solution of 3.15 g (8.6 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate obtained in Stage 1.2 in 100 mL of ethanol and of 26 mL of 2N sodium hydroxide is stirred for four hours under reflux. After this time, the reaction mixture is concentrated at reduced pressure, and then is taken up in 40 mL of water. The reaction mixture is acidified to pH 3 by successive additions of 1N hydrochloric acid. The precipitate is collected by filtration, washed with water and then dried at reduced pressure. Thus, 2.9 g of the expected product is isolated in the form of a white powder, which is used as it is in the next stage.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1)[CH:32]=[CH2:33]
Reactant: C=CCN
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Product: C=CCNc1nccc(Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)n1

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.2 g) and allylamine (0.4 ml) was stirred and heated to reflux for 18 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.135 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 3.5 (m, 4H), 3.7 (m, 4H), 3.82 (m, 2H), 4.95 (m, 1H), 5.05 (m, 1H), 5.85 (m, 2H), 6.57 (br m, 1H), 7.07 (m, 1H), 7.17 (m, 2H), 7.43 (m, 1H), 7.78 (m, 1H), 7.87 (br m, 1H), 8.24 (m, 1H), 8.37 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:7]=1[NH2:8].[F:14][B-:15]([F:18])([F:17])[F:16].[H+]>O>[F:14][B-:15]([F:18])([F:17])[F:16].[Br:13][C:10]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([N+:8]#[N:1])[CH:9]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(Br)cc1N
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1[N+]#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (0.56 g) in water (2.0 mL) was slowly added to a mixture of 2-methyl-5-bromoaniline (1.50 g) in tetrafluoroboric acid (6.0 mL) and water (4.0 mL) at 0-5° C. After addition, the reaction was stirred at room temperature for 30 min. The mixture was cooled to 0° C., filtered, washed with cold water, cold methanol and ether. The mixture was then dried to provide the product 5-bromo-2-methylphenyldiazonium tetrafluoroborate (1.90 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[NH:14][C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]=2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine (150 mg, 0.429 mmol) and potassium carbonate (237 mg, 1.718 mmol) in dry DMF (5 ml) was stirred at 60° C. for 1 hour under an atmosphere of nitrogen and then cooled to room temperature. 4-(3-Bromopropyl)tetrahydro-2H-pyran (0.087 ml, 0.515 mmol) was added and the mixture stirred at 50° C. overnight. The mixture was cooled and partitioned between 1:1 ethyl acetate:DCM (10 ml) and water (10 ml). The organic phase was separated using a hydrophobic frit and evaporated under a stream of nitrogen using a blowdown apparatus. The residue was dissolved in 1:1 methanol:DCM (2.8 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen to give the title compound as a white solid (93.13 mg).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]1[C:28](=[O:53])[C@@H:29]([N:42]1[C:50](=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]1=[O:52])[CH2:30][CH2:31][C:32]([O:34]CC1C=CC=CC=1)=[O:33])=O)C1C=CC=CC=1>CO.[Pd]>[O:51]=[C:50]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43](=[O:52])[N:42]1[C@H:29]([C:28](=[O:53])[N:12]1[C@H:13]([C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:14][CH2:15][CH2:16][NH:11]1)[CH2:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: O=C(CC[C@@H](C(=O)N1[C@H](C(=O)NCCc2ccccc2)CCCN1C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CC[C@@H](C(=O)N1NCCC[C@H]1C(=O)NCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A solution/suspension of (S)-2-[(S)-4-benzyloxycarbonyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyryl]-3-phenethylcarbamoyl-tetrahydro-pyridazine-1-carboxylic acid benzyl ester (1.13 g) and Pd/C (350 mg, 10% on carbon) in MeOH (15 mL, with 2 drops of acetic acid) in a 1,000 mL round flask is vigorously stirred at room temperature, under hydrogen gas (at atmosphere pressure) from a balloon for 3 hours. After degassed by house vacuum for 10 minutes, the reaction mixture is filtered to remove catalyst and concentrated. The crude product is diluted with CH2Cl2/H2O (10 mL, 8/2) and neutralized with 10% NH4OH to Ph=7. After dried and concentrated, the crude product is purified by chromatography (CH2Cl2/MeOH:97/3) to give (S)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-5-((S)-6-phenethylcarbamoyl-tetrahydro-pyridazin-1-yl)-pentanoic acid (0.74 g, 95.3%) as pale solid. (NMR and MS data confirmed, U-3133-63).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH:17]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)(=[O:7])=[O:6])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>O1CCOCC1.O>[CH3:1][C:2]([S:5]([NH:8][CH:9]1[CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH:17]1[N:18]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:6])=[O:7])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC2(CC1NS(=O)(=O)C(C)(C)C)OCCO2
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-N-(8-{[(1R)-1-phenylethyl]amino}-1,4-dioxaspiro[4.4]nonan-7-yl)propane-2-sulfonamide (274 mg, 0.72 mmol) and sodium carbonate (114 mg, 1.074 mmol) in 1,4-dioxane (2 ml) and water (0.4 ml) at 0° C. was added drop wise benzyl chloroformate (CAS number 501-53-1; 0.13 ml, 0.90 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-70% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2([CH3:21])[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16]C)[CH:13]=3)[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[C:1]1([C:7]2([CH3:21])[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([OH:16])[CH:13]=3)[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 175 °C

Procedure:
2-Phenyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (4.94 g., 0.015 mole) is mixed with pyridine hydrochloride (50 g.) and the mixture is heated at 175° C. for 1 hour, then poured into water (500 ml.) and the product is collected and crystallized from ethanol:water, 2:1 to obtain 2-phenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 194°-6° C.