Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][C@H:4]1[CH2:5][OH:6].[C:10]1([CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([CH2:16][CH2:17][CH2:18][C:19]([N:3]2[CH2:9][CH2:8][CH2:7][C@H:4]2[CH2:5][OH:6])=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Aqueous sodium hydroxide (1 N, 25 ml) is added to a solution of 2.0 g of L-prolinol (U.S. patent 3,935,280) in 50 ml of CH2Cl2. After cooling the reaction mixture to 0° C., 4.0 g of 4-phenylbutyric acid chloride is added and the reaction is stirred vigorously for 4 hours at 0° C., followed by 1 hour at room temperature. The reaction is diluted with an equal volume of CH2Cl2 and the layers separated. The organic phase is washed with 30 ml of water and dried over Na2SO4 /K2CO3. The solvent is evaporated to yield 4.4 g of N-(4-phenylbutanoyl)-L-prolinol having IR peaks at 3280 and 1605 cm-1, [α]D25 =-40.3° (methanol). 20.5 g of N-methyl-N,N'-dicyclohexylcarbodiimidium iodide (Angew, Chem., Int. Ed. 11, 229 (1972) is added to a solution of 5.3 of R-(-)-3-benzyloxy-2-methylpropanol (Helv. Chim. Acta 60, 925 (1977) in 200 ml dry tetrahydrofuran under nitrogen and the reaction is stirred at room temperature for 14 hours. The solvent is evaporated and 20 ml of ether and 5 ml of pentane are added. The resulting yellow solid is collected and the mother liquors are chromatographed on 200 g of silica gel with pentane to yield 6.68 g of the S(+)-3-benzyloxy-2-methylpropyl iodide having Rf=0.60 (9:1 of pentane:ether/Si°2), [α ]D25 =+11.1° (MeOH). N-(4-phenylbutanoyl) L-prolinol is dissolved in 2 ml of dry tetrahydrofuran and added dropwise to a solution of lithium diisopropylamide (15.6 m moles) in 50 ml of tetrahydrofuran at 0° C. under nitrogen. After 30 minutes at 0° C., 2.03 g of S-(+)-3-benzyloxy-2-methylpropyl iodide is added dropwise in 2 ml of dry tetrahydrofuran. The reaction is stirred at 0° C. for 5 hours, at -15° C. for 15 hours and quenched at 0° C. with excess saturated ammonium chloride solution. The reaction mixture is diluted with 30 ml of ether. The layers are separated and the organic phase is washed with 16 ml of 1 N HCl, 15 ml of brine, 15 ml of saturated sodium bicarbonate and dried over sodium sulfate. Evaporation of solvent yields 3.6 g of an oil which is filtered through 60 g of silica gel with ethyl acetate to yield 2.3 g of N-(R,R-5-benzyloxy-4-methyl-2-phenethylpentanoyl) L-prolinol having Rf 0.51 (EtoAc/SiO2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:19]1[NH:20][C:21]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[N:31]=[C:32]([NH:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:33]([CH3:39])=[N:34]3)=[CH:22][C:23]=1[C:24]([O:26]CC)=[O:25])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O1CCOCC1.O.[ClH:54]>>[ClH:54].[NH2:11][CH:10]([C:19]1[NH:20][C:21]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[N:31]=[C:32]([NH:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:33]([CH3:39])=[N:34]3)=[CH:22][C:23]=1[C:24]([OH:26])=[O:25])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C(COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(C(N)COCc4ccccc4)[nH]3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a 50-mL round bottomed flask was added ethyl 2-(2-(benzyloxy)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (468b) (0.97 g, 1.61 mmol), LiOH hydrated (0.34 g, 8.04 mmol), dioxane (10 mL), and water (10 mL). The reaction mixture was heated at 100° C. for 24 h and cooled to RT. The solvent was removed and the product used without further purification. The yellow solid obtained was suspended in HCl (10 mL, 4 N in dioxane) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under vacuum and the orange solid obtained was dried to give 2-(1-amino-2-(benzyloxy)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (468c), which was used as crude material and based on theoretical yield.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](OB(C2C=CC=CC=2)O)[CH:24]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[CH:3]=[C:2]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[S:6][CH:5]=3)=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: OB(Oc1cccnc1)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(Br)c1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(-c2cccnc2)c1

Procedure:
The title compound was prepared by coupling 5-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-3-carboxamide with commercially available 3-pyridylphenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 202). HPLC Ret time=1.97 min. LCMS [M+H]+ 378.2.
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=O)[CH2:5][C:4]([F:7])([F:6])[C:3]1([F:9])[Cl:8].S(Cl)([Cl:15])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1([C:10]([Cl:15])=[O:12])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:8])[F:9]
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC1(C(=O)Cl)CC(F)(F)C1(F)Cl
Yield: 75.4 %

Procedure:
One drop of dimethylformamide is added to a mixture 91.2 g (0.45 mol) of 1-methyl-2,3,3-trifluoro-2-chloro-cyclobutane-1-carboxylic acid and 450 ml of chloroform. After this, 80.3 g (0.675 mol) of thionyl chloride are added dropwise at 25°-30° C. with stirring, and the stirred mixture is heated to the boil. After 6 hours the mixture is cooled, the solvent is stripped off, and the residue is subjected to fractional distillation under reduced pressure. 75 g (75% of theory) of 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carbonyl chloride are obtained in form of a liquid of boiling point 65 - 70° C. at 20 mbar. ##STR61## 108.3 g (0.5 mol) of methyl 1-methyl-2-th(oro-2,3,3-trifluoro-cyclobutane-1-carboxylate are added dropwise at 20°-25° C. in the course of 15 minutes to a stirred solution of 127.3 g of potassium hydroxide in 540 ml of methanol. Stirring is continued for 12 hours at 20°-25° C., and part of the methanol is then stripped off under reduced pressure. The residue is diluted with water, and the mixture is extracted using methylene chloride. The aqueous phase is acidified using dilute hydrochloric acid and extracted using methylene chloride. The combined organic phases are dried and concentrated under reduced pressure. 93.3 g of an oil are obtained which consists of 99% 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carboxylic acid. The yield is thus calculated at 90% of theory. 174 g (1.74 mol) of methyl methacrylate and 1.5 g o& hydroquinone are initially introduced into an autoclave, and 200 g (1.74 mol) of trifluorochloroethylene are added at -70° C. 7 bar of nitrogen are injected, and the mixture is then heated to 140° C. The pressure which is established at this temperature is increased to 28 bar by injecting more nitrogen. The mixture is maintained at 140° C. for 17 hours and then allowed to cool, the pressure is released, and the mixture is distilled. In this process, 203 g (54% of theory) of methyl 1-methyl-2-chloro-2,3,3 -trifluoro-cyclobutane-1-carboxylate are obtained in form of a liquid of boiling point 57° C. at 17 mbar.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH:8]12[O:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[C:15]([O:17]C)=O.[Cl-].[NH4+]>O1CCCC1>[CH:8]12[O:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[C:15]1([OH:17])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1CC2CCC1O2
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C2CC3CCC2O3)CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A flask was charged with 14.6 g of magnesium and 270 ml of tetrahydrofuran, to which 64.8 g of 1,4-dibromobutane was added dropwise at 50° C. After the completion of dropwise addition, the solution was stirred at 60° C. for one hour. To the solution below 40° C., 39.0 g of methyl 7-oxa-2-norbornanecarboxylate was added dropwise. The solution was stirred at room temperature for one hour, after which an aqueous solution of ammonium chloride was added for hydrolysis. Ordinary post-treatment yielded 43.7 g of 1-(7-oxanorbornan-2-yl)cyclopentanol.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[N:9]#[N:10].Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH:20]=[C:19]([S:26]([NH:29][C@H:30]([C:38]([N:40]([CH2:45][CH2:46][O:47][CH3:48])[CH2:41][C:42]([Cl:44])=[O:43])=[O:39])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:37])[NH2:36])(=[O:28])=[O:27])[CH:18]=[CH:17]2>>[N:9]#[N:10].[ClH:44].[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][C:42](=[O:43])[CH2:41][N:40]([C:38](=[O:39])[C@H:30]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:36])[NH2:37])[NH:29][S:26]([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[CH:20]=2)(=[O:28])=[O:27])[CH2:45][CH2:46][O:47][CH3:48])[CH:1]=1
Reactant: COCCN(CC(=O)Cl)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reactant: Cc1cccc(O)c1
Agent: Cl
Agent: N#N
Product: COCCN(CC(=O)Oc1cccc(C)c1)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 90 °C
Yield: 86 %

Procedure:
A mixture of 2.00 g of m-cresol and N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl chloride hydrochloride obtained above was heated at 90° C for 50 minutes. At the end of this period, the reaction mixture was cooled, washed several times with dry ethyl ether, and then dissolved in 10 ml of dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a precipitate which was washed several times with dry ethyl ether to give 2.12 g (86 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine m-tolyl ester hydrochloride in the form of a powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[N:7]([CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1.[C:24](O)(C(F)(F)F)=O.C=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl.O1CCOCC1>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=3)[N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:6]=2[CH2:24]1
Reactant: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared by General Method 4. 150 mg of N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine was dissolved in acetonitrile (4 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.04 mL) was added and the reflux was continued for additional 1.5 h. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent Methanol: aqueous NH3, 95:5) to obtain the product. The free base was converted into its dihydrochloride salt by treatment of dioxane-HCl. 1H NMR (DMSO) δ 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (3, 3H), 2.35 (s, 3H). MS m/z observed 320. HPLC RT 3.63 min.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[CH:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]1([CH2:19][C:18]([NH:17][CH:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)CC(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-phenylacetyl-D,L-leucyl-L-proline benzyl ester (2 g) was dissolved in methanol (40 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless sticky matter (1.55 g, 98%), which was directly used for the next reaction.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][N:8]=[C:9]([NH2:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>C(OCC)(=O)C>[NH2:11][C:9]1[N:8]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccco2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Furan-2-yl-2H-pyrazol-5-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using 100% ethyl acetate afforded the title compound as a white solid. 1H NMR (400 MHz, CD6CO); 7.48-7.52 (m, 1H), 6.98-7.06 (m, 2H), 6.52-6.56 (m, 2H), 6.44-6.48 (m, 2H), 5.74 (s, 1H), 4.98 (s, 2H), 3.68-3.88 (m, 4H), 3.12-3.24 (m, 4H). MS (ES) M+H) expected=369.4, found 370.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11]CC)=O)(=[O:4])=[O:3].[NH2:18][CH2:19][CH:20]([OH:31])[CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[OH:31][CH:20]([CH2:21][N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH2:19][NH:18][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: NCC(O)CN1Cc2ccccc2C1
Reactant: CCOC(=O)COc1ccccc1S(C)(=O)=O
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1OCC(=O)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 14 %

Procedure:
Ethyl 2-(2-(methylsulfonyl)phenoxy)acetate (50 mg, 0.19 mmol) and 1-amino-3-(isoindolin-2-yl)propan-2-ol (36 mg, 0.19 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (11 mg, yield 14%) MS (ESI+) e/z: 405.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.98-7.91 (m, 1H), 7.76-7.69 (m, 1H), 7.33-7.24 (m, 2H), 7.21 (d, J=2.76 Hz, 4H), 4.86-4.80 (m, 2H), 4.01-3.97 (m, 4H), 3.97-3.91 (m, 1H), 3.57-3.50 (m, 1H), 3.39-3.35 (m, 1H), 3.30 (s, 3H), 2.86-2.81 (m, 1H), 2.81-2.74 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](=[O:22])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(-c2cccs2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(-c3cccs3)n2)sc2ccccc12
Yield: 86.8 %

Procedure:
6-(2-Thienyl)-2-pyridinecarbonitrile (0.56 g, 3.0 mmol) and methyl thiosalicylate (0.77 g, 4.6 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 10 hrs. After cooling, the precipitates were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.84 g, 86%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Br:32])[C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](Cc1cc(Br)c(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester (7.6 g, 21 mmol) was dissolved in acetic acid (100 mL). Sodium acetate (4.2 g, 51 mmol) was added to the solution. Reaction vessel was placed in a cool water bath to control reaction exotherm. Bromine (1.1 mL, 22 mmol) was added to the mixture in one portion. Reaction stirred at ambient temperature for 10 minutes. Mixture was poured into 1N aqueous sodium thiosulfate solution (400 mL). Material was extracted twice with ethyl acetate. Organic phase was washed successively with water and brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 77% yield as an amber oil. MS m/e (M−H)−=440.0, 442.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:35][CH2:36][O:37][Si:38]([CH3:41])([CH3:40])[CH3:39]>C1COCC1.CN(C=O)C>[C:17]([CH:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[C:2]2[N:3]([CH2:35][CH2:36][O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:12][CH2:13]1)([CH3:18])([CH3:19])[CH3:20]
Reactant: C[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc(CN(c2nc3ccccc3[nH]2)C2CCC(C(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(c2nc3ccccc3n2CCO[Si](C)(C)C)C2CCC(C(C)(C)C)CC2)cc1
Temperature: 40 °C

Procedure:
To the title compound from Example 1 Step C (0.5 mmol, 210 mg) in 1 mL of THF was added a solution of NaH (1 mmol, 40 mg of 60% slurry in mineral oil) in 1 mL of DMF (exothermic, H2 evolution). After gas evolution ceased for several minutes, (2-bromoethoxy)(trimethyl)silane was added to the solution via syringe. The reaction mixture was heated to 40° C. After 2.5 h the reaction was quenched by addition of saturated ammonium chloride. The product was extracted 3× with EtOAc and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica eluting with 5% EtOAc/hexanes. HPLC A: 3.14 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].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]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:22]#[N:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Heat a solution of 4-(5-bromo-3-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 14.0 mmol), Zn(CN)2 (989 mg, 8.4 mmol) and Pd(PPh3)4 (970 mg, 0.84 mmol), in dry DMF (50 mL) at 80° C. for 16 h under nitrogen in a sealed tube. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound, and use immediately for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>C(#N)C>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:26])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Temperature: 0 °C

Procedure:
The mixture of 1.7 g 2-amino-3-cyano-4-hydroxy-6-(4-acetylpiperazin-1-yl)quinoline, 50 ml acetonitrile and 3.4 ml phosphoryl chloride is heated at reflux temperature for 4 hours. The cooled reaction mixture is poured onto 30 g ice, the pH of the mixture is set to 8 with 10% sodium hydroxide solution and the resulting precipitate is filtered off. After drying 1.5 g of the title compound is obtained (MH+: 330).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[N:3]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:24]/[CH:25]=[O:26])=[CH:10][CH:9]=2)[N:3]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ccnc(-c2ccc(C=O)cc2)n1
Product: Cc1ccnc(-c2ccc(/C=C/C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 14) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11](Cl)=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C(O[C:23](=[O:38])[CH2:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:10][C:9]=1[NH:18][C:23](=[O:38])[CH2:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C#Cc1ccccc1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) according to the general procedure M. Obtained as an orange solid (148 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cccc(F)c2F)CCNC1
Reaction time: 3 h

Procedure:
Preparation according to Preparation 2: tert-butyl 3-(2,3-difluorophenyl)-3-hydroxy-pyrrolidin-1-carboxylate (1.72 g, 5.75 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 3 h. Yield: 0.31 g. MS m/z (rel. intensity, 70 eV) 199 (M+, bp), 141 (87), 127 (60), 114 (38), 113 (63).