Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([O:35]C)=[O:34])(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([OH:35])=[O:34])(=[O:30])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Prepared using General Procedure 7: To a stirring solution of (R)-methyl 2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetate INT-14 (0.082 g, 0.16 mmol) in MeOH (1.5 mL) was added 6N NaOH (0.08 mL). The reaction was stirred at room temperature for 6 h. The crude reaction was diluted with water, acidified with 1N HCl and extracted with DCM and EA. The organic layer was dried over Na2SO4, concentrated, and isolated after preparative HPLC purification to give 0.057 g (72%) of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetic acid 34. An analytically pure sample was prepared by preparative HPLC purification. LCMS-ESI (m/z) calculated for C24H26N4O6S: 496.5; found 520.1 [M+Na]+, tR=3.47 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH3:22])[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:27]>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH:20]([OH:27])[N:19]([CH3:22])[C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
12.56 g of 5-{[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene}-3-methyl-4-thiazolidinone, 1-oxide (the compound of Example 12) was dissolved in 216 ml of methylene chloride and the resultant solution cooled to -78° C. Separately, 6.1 ml of trifluoroacetic anhydride and 72 ml of methylene chloride were placed in a dropping funnel and the solution added dropwise over a 40-minute period (temperature maintained at or below -70° C.) to the previously prepared solution of the compound of Example 12 in methylene chloride. The resulting reaction mixture was stirred at -75° C. for 1 hour, then warmed to 0° C. over 45 minutes, diluted with a volume of methylene chloride, washed with two volumes of water, dried over sodium sulfate and subsequently filtered and evaporated to give 15.8 g of the desired titled product and trace impurities. This product was dissolved in 25 ml of warm ethyl acetate and then added to 450 ml of hexane. As the solution cooled, it became milky and an additional 5 ml of ethyl acetate was added and swirled to clarify. The solution was then allowed to cool to room temperature with precipitate forming overnight. The precipitate was collected by filtration, washed with hexane and dried at room temperature in vacuo overnight. The resultant product was further worked up by adding it to 30 ml of hot ethyl acetate, to which was added an additional 150 ml of hexane. A precipitate began to form. The mixture was allowed to cool to room temperature and stand for 6 hours, after which it was filtered, washed with a volume of hexane and dried in vacuo at 50° C. overnight to render 8.83 g of the desired titled product, m.p. 165°-170° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:3].[NH:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:20]([C@H:25]([CH2:27][C:28](O)=[O:29])[OH:26])[CH2:21][CH:22]([CH3:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:19]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:20]([C@H:25]([CH2:27][C:28]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[OH:13])[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:5])[CH3:3])=[O:29])[OH:26])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
960 mg of H-Ala-Sta-OMe, 1 g of Boc-Sta-OH, 420 mg of HONSu and 750 mg of DCCI are dissolved successively in 50 ml of CH2Cl2 at RT. A white precipitate appears very quickly. The mixture is stirred at RT and, after 7 h, the DCU formed is filtered off and washed with CH2Cl2. The organic solution is washed successively with KHSO4 --K2SO4 (5% solution in H2O) and NaHCO3 (5% solution in H2O). It is dried over MgSO4 and filtered and the solvent is evaporated off. The product is solubilized in the minimum quantity of a chloroform/MeOH mixture (97.5/2.5, vol/vol) and deposited on the top of a column of silica gel; elution is carried out with the same mixture and the eluate is fractionated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][NH:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][NH:10][C:11]1[CH:16]=[C:15]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([F:34])([F:35])[F:33])=[C:26]([F:25])[CH:27]=2)[N:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CNc1cc(Cl)ncn1)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
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+]
Product: CC(C)(C)OC(=O)N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(F)c2)ncn1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
[2-(6-Chloro-pyrimidin-4-ylamino)-1-phenyl-ethyl]-carbamic acid tert-butyl ester (87 mg, 0.25 mmol), 3-fluoro-4-(trifluoromethyl)-phenyl boronic acid (57 mg, 0.28 mmol), Pd(PPh3)4 (2.9 mg, 2.5 μmol) and K3PO4 (110 mg, 0.50 mmol) were placed in a sealed tube which was evacuated and refilled with N2. 1,2-Dimethoxyethane (2 mL) and water (0.5 mL) were added to the sealed tube. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was cooled to rt and was filtered through a pad of MgSO4. The pad was washed with CH2Cl2. The crude filtrate was concentrated under reduced pressure and the residue was purified via reverse phase chromatography to yield the title compound (87.0 mg, 59%).
Reaction SMILES: [OH-].[NH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3cccc(C(F)(F)F)c3)c21
Reaction time: 1 h
Yield: 42 %

Procedure:
In 150 ml of toluene and 700 of 30% potassisum hydroxide were combined 3.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 0.72 g of tetrabutylammonium hydrogen sulfate. The reaction was mechanically stirred and heated with a steam bath. To it was added dropwise a solution of 13.5 g 3-trifluoromethylbenzyl bromide in 30 ml of toluene over 1 hour. After the addition, heating was continued 1 hour during which the reaction went to completion. The organic phase was separated, washed with ice-cold saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was diluted with 10 ml of ethyl acetate and purified by preparative HPLC (ethyl acetate). The product-containing fractions were evaporated and recrystallized from DCM/hexane to yield 2.20 g of solid, mp 147°-149° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10].Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][OH:21])[C:15]=1[CH3:22]>O>[SH:10][CH2:9][CH2:8][CH2:7][S:11][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][OH:21])[C:15]=1[CH3:22]
Reactant: Cc1c(Cl)ccnc1CO
Reactant: SCCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(SCCCS)ccnc1CO
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
A solution of potassium carbonate (691 g, 5 mol) in 1.5 l of water is treated with 1,3-propanedithiol (432.8 g, 4 mol) under a nitrogen atmosphere and heated to 80° C. A solution of (4-chloro-3-methylpyridin-2-yl)methanol hydrochloride (194.1 g, 1 mol) in 400 ml of water is then added dropwise at this temperature with vigorous stirring during the course of about 2 h. The mixture is additionally stirred at 80 to 85° C. for 18 h and then cooled to room temperature. After separating off the aqueous phase, the organic phase is treated with toluene (1.5 l) and washed with water (2×1 l). The organic phase is then extracted with 2M hydrochloric acid (2 l). The hydrochloric acid phase is concentrated and the residue is recrystallized from isopropanol. 159 g (60%) of the title compound are isolated. The crude product is employed without further purification for the synthesis of the compound of Example 1.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.CO.[ClH:31].CCOCC>>[ClH:31].[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(OCc1ccc(OC(F)(F)F)cc1)N1CCNCC1

Procedure:
A solution of 174 mg (0.49 mmol) piperazine-1,4-dicarboxylic acid tert-butyl ester 4-trifluoromethoxy-benzyl ester in 4.9 ml 1.5M HCl/Et2O and 0.98 ml abs. MeOH was stirred at rt for 3 h. Evaporation of the reaction mixture provided 189 mg as colourless powder. 1H-NMR (d6-DMSO): 3.10 m, 4H and 3.62 m, 4H; 5.13 2, 2H; 7.40 d, 2H and 7.53 d, 2H, AB-system; 9.2 br, 2H. MS (ISP): 305.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: [H][H]
Reactant: CC(C)Cn1cnc2c(N)nc3cccnc3c21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)NCCC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.46 g) in trifluoroacetic acid (10 mL). The reaction mixture was reduced on a Parr apparatus under 45 psi (3.15 Kg/cm2) hydrogen pressure for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added. The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a solid, m.p. 222-226° C. Analysis: Calculated for C13H19N5: % C, 63.65; % H, 7.81; % N, 28.55; Found: % C, 63.07; % H, 7.51; % N, 28.00.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:23][CH2:24][N:25]=3)[C:8]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[N:9][C:10]=2[C:11]=1[O:12][CH3:13].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:44][C@@H:45]1[O:47][CH2:46]1)(=O)=O>CN(C=O)C>[CH3:13][O:12][C:11]1[C:10]2[N:9]=[C:8]([NH:14][C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[N:7]3[CH2:23][CH2:24][N:25]=[C:6]3[C:5]=2[CH:4]=[CH:3][C:2]=1[O:1][CH2:44][C@H:45]1[CH2:46][O:47]1
Reactant: CS(=O)(=O)OC[C@H]1CO1
Reactant: COc1c(O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(OC[C@H]2CO2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of N-{8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide (Intermediate I, Step 2 (used as bis-TFA salt), 1.50 g, 2.65 mmol) and caesium carbonate (4.32 g, 13.3 mmol, 5.0 equiv.) in DMF (37 mL) was stirred at room temperature for 1 h, then was treated with (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 21.2 mL, 0.25 M in DMF, 5.31 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 16 h at 60° C., then was cooled to room temperature and concentrated under reduced pressure. The resulting residue was seperated between water (50 mL) and a 4:1 CH2Cl2/isopropanol solution (50 mL). The organic phase was washed with a concentrated sodium bicarbonate solution, dried (anh. sodium sulfate), and concentrated under reduced pressure. The resulting material was triturated with EtOH and dried under reduced pressure to give N-{7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide (0.72 g, 69%): HPLC ret. time 0.94 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.75 (dd, J=2.5, 5.1 Hz, 1H), 2.88 (app t, J=4.7, 1H), 3-42-3.47 (m, 1H), 4.01 (s, 3H), 4.14 (dd, J=6.6, 11.6 Hz, 1H), 4.20-4.29 (m, 3H), 4.52-4.59 (m, 2H), 4.68 (dd, J=2.3, 11.6 Hz, 1H), 7.47 (d, J=9.4 Hz, 1H), 7.92 (dd, J=5.6, 7.8 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.90 (br d, J=7.8 Hz, 1H), 8.97 (dd, J=1.5, 5.6 Hz, 1H), 9.49 (d, J=1.5 Hz, 1H); mass spectrum m/z 394 ((M+1)+, 11%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:12][NH2:13].[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:12][NH:13][CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: O=C1CCSCC1
Reactant: NCc1ccc(F)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(CNC2CCSCC2)cc1Br
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a solution of tetrahydro-4H-thiopyran-4-one (1.16 g) in chloroform (50 mL), 3-bromo-4-fluorobenzylamine (2.41 g) was added and the resulting mixture was stirred at room temperature for an hour. Sodium (triacetoxy)borohyride (6.36 g) was added and the resulting mixture was stirred overnight. To the reaction mixture, an aqueous solution of 2 M sodium hydroxide was added and after stirring the resulting mixture, extraction was performed with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=100:0 to 99:1) to give the titled compound (1.72 g).
Reaction SMILES: [OH:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[H][H]>C(O)C.[Pd]>[NH2:13][C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CN(C)C(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1cccc(N)c1O
Yield: 101 %

Procedure:
A solution of 33.5 g of 2-hydroxy-N,N-dimethyl-3-nitrobenzamide in 600 ml of ethanol were added to a suspension of 3.35 g of Pd/C 10% in 70 ml of ethanol. The reaction medium was stirred under 2 bar of hydrogen overnight. TLC and HPLC control (t=0.66 M+181). The reaction medium was filtered through celite and the filtrate was evaporated. 29 g of 3-amino-2-hydroxy-N,N-dimethylbenzamide were obtained in the form of an oily brown solid. Yield=100%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH2:7][O:8][CH3:9])=[O:6].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CCCCCCC>[CH3:13][N:14]([CH:16]=[C:4]([C:5](=[O:6])[CH2:7][O:8][CH3:9])[C:3]([O:2][CH3:1])=[O:10])[CH3:15]
Reactant: COCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Solvent: CCCCCCC
Product: COCC(=O)C(=CN(C)C)C(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
Methyl-4-methoxyacetoacetate (9 ml, 70 mmol) was added to dimethylformamide dimethylacetal (18.8 ml, 139 mmol) and the reaction stirred at 90° C. for 2 hours before cooling to room temperature and stirring for 18 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography, eluting with 70:30 to 100:0 ethyl acetate:heptane to afford the title compound as an oil (7.68 g, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH:14]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH:14]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoate of example 11 (0.3 g) is dissolved in 10 ml of methanol, 20 ml of 1N aqueous NaOH added and the reaction is stirred at room temperature overnight. The methanol is evaporated off, water added and the mixture extracted with ethyl acetate. The aqueous layer is acidified to pH 6.1 and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoic acid, NMR (CDCl3): delta 7.7 (d,2H), 7.4 (d,2H), 2.9 (m,2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:6][CH:5]([CH3:7])[C:4](=[O:8])[N:3]1[CH2:9][C:10]([NH2:12])=[O:11].[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26]([N:6]1[CH:5]([CH3:7])[C:4](=[O:8])[N:3]([CH2:9][C:10]([NH2:12])=[O:11])[C:2]1([CH3:1])[CH3:13])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1NC(C)(C)N(CC(N)=O)C1=O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CC1C(=O)N(CC(N)=O)C(C)(C)N1C(=O)CNC(=O)OCc1ccccc1

Procedure:
The same procedure of Example 2, starting from 2,2,4- trimethyl-5-oxo-1-imidazolidineacetamide and N-benzyloxycarbonylglycine, afforded 3-(2-benzyloxycarbonylaminoacetyl)-2,2,4-trimethyl-5-oxo-1-imidazolidineacetamide, as an oil, then the title compound, m.p. 118° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=212 (M.+ --CH4N), 184 (M.+ --C2H4NO).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[OH:13][C:14]1[C:23]([CH2:24][CH:25]=[CH2:26])=[C:22]([CH3:27])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>O>[C:1]([O:13][C:14]1[C:23]([CH2:24][CH:25]=[CH2:26])=[C:22]([CH3:27])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1c(C)ccc(C(=O)OC)c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCc1c(C)ccc(C(=O)OC)c1OC(C)=O

Procedure:
351 g of acetic anhydride followed by 2.5 ml of sulphuric acid (d=1.84) in small amounts, and finally, 355 g of methyl 2-hydroxy-3-allyl-4-methylbenzoate were introduced into a 2-liter round-bottomed flask. The temperature rose up to 35° C. The contents were heated under reflux for 3 hours and the solution obtained was then poured into 2 liters of iced water. The oily layer formed was decanted and extracted with ether and the solution containing ether was dried over sodium sulphate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:41])[CH3:40])=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Product: CC(=O)Nc1ccc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2-c2ccc(C)cc2)nc1

Procedure:
N-{6-{2-(5-Aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)-pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and acetic anhydride are treated in the same manner as in Example 135 to give N-[6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl]acetamide.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(Cl)c(F)c3)c2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(Cl)c(F)c2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 40.9 %

Procedure:
An ice cold solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (21 mg, 0.055 mmol) in N,N-Dimethylformamide (DMF) (500 μl) was treated with K2CO3 (37.9 mg, 0.275 mmol), DIEA (47.9 μl, 0.275 mmol), and 4-chloro-3-fluorobenzyl bromide (61.4 mg, 0.275 mmol), stirred at rt for 1 hr, and then heated to 70° C. for 18 hours. The reaction was diluted with water, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-chloro-3-fluorobenzyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (26.2 mg, 0.050 mmol, 91% yield) as clear oil. The ester intermediate was dissolved in Methanol (500 μl) and Tetrahydrofuran (THF) (500 μl), treated with 2M LiOH (150 μl, 0.3 mmol), and stirred at 60° C. for 2.5 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA, 12 min) to give title compound (11.6 mg, 0.022 mmol, 40.9% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.43 (s, 3H), 3.65 (s, 3H), 5.46 (s, 1H), 5.79 (d, J=2.3 Hz, 2H), 6.06 (d, J=2.8 Hz, 1H), 6.94-7.07 (m, 3H), 7.24-7.31 (m, 2H), 7.30-7.38 (m, 2H), 7.49-7.56 (m, 1H); LCMS (m/z) ES+=511 (M+1).