Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH:15]([NH:17][C:18](=O)[CH3:19])[CH3:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3>P(Cl)(Cl)(Cl)=O>[CH3:19][C:18]1[N:8]2[C:7]3[C:2]([CH3:1])([O:3][CH2:4][CH2:5][C:6]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:15]([CH3:16])[N:17]=1
Reactant: CC(=O)NC(C)C1(C)OCCc2c1[nH]c1ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NC(C)C2(C)OCCc3c2n1c1ccccc31

Procedure:
A mixture of N-[1-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)ethyl]-acetamide (2.0 g, described in Example 2) and phosphorus oxychloride (10 ml) is heated at 100°-110° C. for 3 hours and evaporated. The residue is partioned between chloroform and 10% sodium carbonate. The organic layer is collected, washed with water, saturated brine solution and dried over magnesium sulfate. The residue is chromatographed on silica gel using chloroform. The eluates are evaporated to give a less polar isomer, isomer A(0.40 g), of the title compound, nmr(CDCl3) δ 0.86 (d) and 3,74 (q) and a more polar isomer, isomer B(0.40 g), of the title compound nmr(CDCl3) δ 0.78 (d) and 4.07 (q).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][N:22]([O:23][CH3:24])[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC(=O)O)CC1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.4 %

Procedure:
A solution of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-butanoic acid (291 mg, 1.07 mmol, from Step A), N,O-dimethylhydroxylamine hydrochloride (177 mg, 1.82 mmol), EDC (350 mg, 1.82 mmol), and triethylamine, 0.25 mL, 1.82 mmol) were stirred together in 5 mL CH2Cl2 for 16 h. The mixture was diluted with 100 mL CH2Cl2 and washed with 1M HCl. The organic layer was dried over MgSO4 and concentrated. Flash chromatography (1/1 hexane/EtOAc) afforded 237 mg (71%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=[O:6].O.[OH-].[Li+]>CO.O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[CH2:3][CH:4]([CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(CC(F)(F)F)C(=O)O
Reaction time: 48 h
Yield: 99.6 %

Procedure:
A solution of ethyl 4,4,4-trifluoro-2-methylbutyrate (7.7 g) in methanol (21 mL), tetrahydrofuran (21 mL) and water (8.4 mL) was treated with lithium hydroxide monohydrate (3.5 g). The mixture was stirred for 48 hours and the organic solvents evaporated. The resulting aqueous solution was diluted with water and acidified with 6N hydrochloric acid. The aqueous solution was exhaustively extracted with ethyl acetate. The combined organic extract was washed (water and brine), dried (MgSO4), filtered and evaporated to give 4,4,4-trifluoro-2-methylbutyric acid as a pale yellow liquid (6.5 g, 99%); partial NMR (300 MHz, CDCl3): 1.34 (d, 3H, CH3), 2.18 (m, 1H, H-C(3)), 2.67, (m, 1H, H-C(3)), 2.74 (m, 1H, H-C(2)), 10.6 (br, 1H, CO2H).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(O)(=O)C>O1CCCC1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: c1ccsc1
Reactant: COc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (12.5 ml of 1.6N in hexanes) was added to a stirred solution of thiophene (1.68 g) in dry tetrahydrofuran (80 ml). The mixture was stirred at room temperature for 0.5 h and then a solution of 4-methoxybenzylbromide (2.62 g) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred for 1 h and then acetic acid (1.2 ml) was added and the solvent evaporated. The residue was partitioned between ethyl acetate and water, the organic phase was washed with water and brine dried over magnesium sulphate and evaporated. The product was isolated by column chromatography (Kieselgel:hexane). δ(CDCl3) 3.80 (3H, s), 4.10 (2H, s), 6.78-6.94 (4H, m), 7.13-7.20 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3n2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Yield: 9.4 %

Procedure:
2-(4-Nitrophenylthio)quinoline (0.42 moles, 12.0 g) was hydrogenated in 300 ml DMF over 5.0 g Pd/C for 3 hr at room temperature. The solution was filtered through celite and concentrated. The product was triturated with ether and hexane to yield 2-(4-aminophenylthio)quinoline 10.0 g, 93%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>>[C:14]([C:6]1[N:2]([CH3:1])[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]=1[CH3:7])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Temperature: 25 °C
Yield: 56.2 %

Procedure:
Ethyl 1,4-dimethylpyrrole-2-acetate (37.0 g, 0.19 mol), benzoyl chloride (54.3 g, 0.38 mol), and triethylamine (52.9 ml, 0.38 mol) were dissolved in xylenes (750 ml), and the reaction mixture was refluxed for 18 h under argon. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Purification on a Florisil® column (hexane followed by hexane-ethyl acetate, 4:1) gave ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (30.45 g, 57%) as a solid. ##STR19##
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:18]=[CH:17][C:16]([C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.C(=O)=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>O1CCCC1>[C:13]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:14]=[CH:15][C:16]([C:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:20][C:21]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:22])=[CH:17][CH:18]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(-c3ccccc3)cc2)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(-c3ccccc3)cc2)cc1OC
Reaction time: 1 h
Yield: 55.3 %

Procedure:
4.7 g of carbonyldiimidazole were added in portions to a solution of 9.4 g of 3-(biphenyl-4-yl)-3-(3,4-dimethoxyphenyl)acrylic acid in 50 ml of anhydrous tetrahydrofuran. After the evolution of CO2 had subsided, 2.5 g of morpholine were added, and the mixture was boiled for 1 hour. After evaporation, the residue was taken up in toluene/water, and the aqueous phase was discarded. The organic phase was washed once more with water, then dried and evaporated. The crude title compound was isolated with a yield of 10.5 g. The crude product was purified on silica gel with toluene/ acetone (9:1). 6.2 g of the title compound were obtained in the form of a yellow resin, Rf: 0.56 ]l (silica gel, toluene/ acetone 7:3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O[Na])(C)=O.O.O.O.CC(O)=O>CO.O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:3][C:2]=1[Br:1]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc(N)c(Br)c1
Temperature: 90 °C
Yield: 68.6 %

Procedure:
A mixture of methyl 3-bromo-4-nitrophenylacetate (14.8 g, 53.8 mmol), reduced iron powder (9.62 g, 172 mmol), AcONa.3H2O (7.32 g, 53.8 mmol) and AcOH (20.0 ml) in MeOH/H2O (150/600 ml) was heated at 90° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through Celite and the filtered cake was washed with MeOH. The combined filtrate were evaporated and extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [400 g, CHCl3/EtOAc (20/1)] to give methyl 4-amino-3-bromophenylacetate (9.01 g, 69%) as a brown oil. 1H-NMR (CDCl3) δ 3.48 (s, 2H), 3.68 (s, 3H), 4.05 (br, 2H), 6.69 (d, J=8.3 Hz, 1H), 7.00 (dd, J=8.1, 2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:17]([C:14]3[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=3)(=[O:19])=[O:18])[CH:9]=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine (15 g, 76 mmol) and p-toluenesulfonyl chloride (21.77 g, 114 mmol) in toluene (200 mL) was added a solution of tetrabutylammonium hydrogen sulfate (2.58 g, 7.61 mmol) in water (10 mL) and the mixture was cooled to 0° C. A solution of sodium hydroxide (9.13 g, 228 mmol) in water (30 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the solution was washed with saturated sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 352 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([NH2:26])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[C:24]([NH2:26])=[O:25])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)C1CCCCN1
Product: NC(=O)C1CCCCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 2-piperidinecarboxamide (CAN 19889-77-1, 60.4 mg, 472 μmol) as starting materials and isolated (135 mg, 92%) as white solid; LC-MS (UV peak area, ESI) 100%, 344.1972 [MH+].
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:39])[N:24]([CH:35]2[CH2:38][CH2:37][CH2:36]2)[CH2:25][CH2:26][C:27](=[O:34])[NH:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:19]([Cl:40])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:40][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:35]1[CH2:36][CH2:37][CH2:38]1)[CH2:25][CH2:26][C:27](=[O:34])[NH:28][CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:39]
Reactant: CC(C)(C)CNC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CNC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCC1
Reaction time: 64 h

Procedure:
A solution of [2-(3-chloro-5-{cyclobutyl-[2-(2,2-dimethyl-propylcarbamoyl)-ethyl]-carbamoyl}-phenoxy)-ethyl]-pyridin-4-yl carbamic acid tert-butyl ester (0.016 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64 h and then concentrated under reduced pressure to give the title compound (0.012 g) as a colourless gum.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][NH2:17])=[N:14][CH:15]=2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=[C:19]1[CH2:23][S:22][CH2:21][CH:20]1[C:24](OC)=[O:25]>>[C:1]([C:5]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:24](=[O:25])[C:20]4[CH2:21][S:22][CH2:23][C:19]=4[NH:17]3)=[N:14][CH:15]=2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1noc(-c2ccc(NN)nc2)n1
Reactant: COC(=O)C1CSCC1=O
Product: CC(C)(C)c1noc(-c2ccc(-n3[nH]c4c(c3=O)CSC4)nc2)n1
Yield: 36.4 %

Procedure:
According to the process described in Example 1, starting with 0.6 g of 5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-hydrazinylpyridine and 0.41 g of methyl 4-oxotetrahydrothiophene-3-carboxylate, 0.32 g of 2-[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27](=[O:40])[N:28]([CH3:39])[N:29]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:31]=[C:30]4[C:26]([C:27](=[O:40])[N:28]([CH3:39])[N:29]4[C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:25][CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Product: CC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
89 mg (purity 83%, 0.24 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 75 mg (56% of theory)
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:7]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=2[C:9](O)=[O:10])=O)[CH2:3][CH2:2]1.O.[NH2:19][NH2:20]>>[CH:1]1([CH2:4][C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:10])[NH:20][N:19]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C(=O)CC2CC2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(CC3CC3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(2-cyclopropylacetyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: Br[C:2]1[N:3]([CH3:8])[CH:4]=[C:5]([Br:7])[N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>ClCCl>[Br:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]([CH3:8])[CH:4]=1
Reactant: C1CNCCN1
Reactant: Cn1cc(Br)nc1Br
Solvent: ClCCl
Product: Cn1cc(Br)nc1N1CCNCC1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
A 20-mL resealable tube was charged with 2,4-dibromo-1-methyl-1H-imidazole (0.480 g, 2.00 mmol) and piperazine (3.4 g, 39.5 mmol), and the resulting mixture was stirred for 3 h at 130° C. The reaction mixture was cooled to room temperature, diluted with dichloromethane (20 mL), washed with water (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-(4-bromo-1-methyl-1H-imidazol-2-yl)piperazine (0.300 g, 61%) as a light yellow solid. MS (ESI, pos. ion) m/z 245, 247 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>ClCCl>[CH:13]1([NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: Fc1ccc2c(Cl)ncnc2c1
Solvent: ClCCl
Product: Fc1ccc2c(NC3CC3)ncnc2c1
Yield: 36.9 %

Procedure:
4-Chloro-7-fluoro-quinazoline (0.73 g, 4 mmol) and cyclopropylamine (0.23 g, 4 mmol) are stirred in dichloromethane at ambient temperature overnight. The solid product is precipitated with hexanes, filtered, and washed with hexane and ethyl acetate, affording 0.3 g of desired Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine. The filtrate is concentrated and precipitated with hexanes, yielding an additional 0.35, for a combined yield of 80%. LC/MS m/z=204 [M+H]+).
Reaction SMILES: COCCOCC[C:8]1(CCOCCOC)[C:20]2[CH:19]=[C:18](C=C)[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][C:11](C=C)=[CH:12][CH:13]=2.CC(N=NC(C#N)(C)C)(C#N)C>O.C1COCC1>[CH:10]1[C:9]2[CH2:8][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccc2c(c1)C(CCOCCOC)(CCOCCOC)c1cc(C=C)ccc1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccccc1-2
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A mixture of the polymeric macroinitiator, 7 (2.0 g, 0.22 mmol, Mw) 7700, PDI) 1.11), 3 (0.668 g, 1.55 mmol), and AIBN (0.43 mg, 0.03 mmol) was dissolved in 2% H2O in THF (6.0 mL), degassed by four freeze/pump/thaw cycles, and sealed under argon. The polymerization mixture was then stirred at 85° C. for 48 h and allowed to cool, and the star polymer, 23, was obtained after precipitation using ethyl acetate followed by dialysis against methanol (1.9 g, 71%, Mw) δ 500, PDI) 1.32). 1H NMR (CDCl3): δ (ppm) 7.10-7.28 (br m, ArH), 5.03 (br s, CH), 4.35 (br s, CH2), 2.68 (br s, CH2), 2.42 (br s, CH2), 1.95 (br s, CH2), 1.50-1.85 (br m, CH2).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[OH:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(#N)C>[CH2:23]([NH:27][C:28]([O:22][CH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN=C=O
Reactant: O=C1c2cccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OC1c2ncccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 3 h

Procedure:
A suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-hydroxy-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1 g.) in acetonitrile (100 cc.) containing n-butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) is heated at the reflux temperature for 1 hour 30 minutes. n-Butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) are then added and heating at the reflux temperature is continued for a further 3 hours. The solution is filtered and the filtrate is concentrated under reduced pressure (40 mm.Hg). The residue obtained is triturated with diisopropyl ether (20 cc.). The solid is filtered off and is recrystallised from acetonitrile (35 cc.) to give 7-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.96 g.) melting at 215° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([C:20]([OH:22])=O)[NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:12])[CH:3]=1.[C:23](OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:20]([CH:9]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:12])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:22])[CH3:23]
Reactant: Cc1ccc(C(=O)NC(Cc2cccc(Br)c2)C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)C(Cc1cccc(Br)c1)NC(=O)c1ccc(C)cc1
Reaction time: 3 h

Procedure:
1-Bromo-3-[2-carboxy-2-(p-toluoylamino)ethyl]benzene (16.84 g) was dissolved in 85 ml of pyridine, and 55 ml of acetic anhydride was added and stirred for 3 hours under argon atmosphere at 90–95° C. Water (55 ml) was added dropwise gradually so that the maximum temperature did not exceed 100° C., and the mixture was stirred for 20 minutes at 60–70° C. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The resulting solution was washed with 10% hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate solution sequentially and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting crystals were washed with isopropyl ether to provide 13.31 g of the objective compound as brownish crystals. M.p. 106–107° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[C@H:13]([O:18][CH3:19])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:19][O:18][C@H:13]1[C@@H:14]([O:16][CH3:17])[CH2:15][NH:11][CH2:12]1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OC
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CNC[C@H]1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of 3,4-cis-dimethoxy-pyrrolidine-1-carboxylic acid benzyl ester 5b (16.95 g, 63.9 mmole) in MeOH (150 ml) was added 10% Pd on C (1.3 g). The mixture was stirred under H2 balloon at room temperature for 3 hours and filtered through celite. The filtrate was concentrated, in vacuo, re-dissolved in CH2Cl2 and dried over Na2SO4. The solution was concentrated to give 8.3 g (99%) of a yellow oil. 1H NMR (300 MHz, CDCl3) δ3.80 (2H, m), 3.47 (2H, bs), 3.41 (6H, s), 3.01 (2H, bs).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br-].C(OCC[N+]1C(C)=C(CCO)SC=1)C.[CH2:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH:42]=[O:43])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]>O1CCOCC1>[CH2:30]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH2:40][CH2:41][C:42](=[O:43])[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:38][CH2:39]1)[CH2:31][CH2:32][CH3:33]
Reactant: C=CC(=O)OCC
Reactant: CCCC[C@H]1CC[C@H](CCC=O)CC1
Agent: CCOCC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCC[C@H]1CC[C@H](CCC(=O)CCC(=O)OCC)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
7.5 g of ethyl acrylate are dissolved in 100 ml of dry dioxan under nitrogen gasification, treated with 6.1 g of triethylamine and 1.4 g of 3-(2-ethoxyethyl)-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide and heated to 80° C. A solution of 19.6 g of 3-(trans-4-butylcyclohexyl)propanal and 7.5 g of ethyl acrylate in 50 ml of dioxan is added dropwise within 5 hours. The mixture is stirred at 80° C. for a further 15 hours, then cooled to room temperature and freed from solvent on a rotary evaporator. The residue is taken up in 200 ml of tert.butyl methyl ether and washed successively with dilute sulphuric acid, dilute sodium hydrogen carbonate solution and water. The aqueous phases are back-extracted with 100 ml of tert.butyl methyl ether. The combined organic phases are dried over sodium sulphate and freed from solvent on a rotary evaporator. The crude product of ethyl 6-(trans-4-butylcyclohexyl)-4-oxo-caproate obtained is recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[C:19]([O-])([O-])=O.[K+].[K+].CB(O)O>O1CCOCC1.O.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>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1scc(Br)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1scc(Br)c1C
Temperature: 70 °C
Yield: 83.4 %

Procedure:
To a solution of methyl 4-bromo-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (825 mg, 2.25 mmol) in dioxane/H2O (5 mL/1 mL) was added K2CO3 (930 mg, 6.75 mmol), tetrakistriphenylphosphine Pd(0) (260 mg, 0.22 mmol), and methylboronic acid (175 mg, 2.91 mmol). The reaction mixture was heated to 70° C. in a sealed tube for 12 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 9:1) to give the title compound (441 mg, 84%) as a brown solid: LC-MS (ES) m/z 236 (M+H)+.