Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].[CH2:35]([N:37]([CH2:42][CH3:43])[C:38](=[O:41])[CH2:39]Cl)[CH3:36]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:39][C:38](=[O:41])[N:37]([CH2:42][CH3:43])[CH2:35][CH3:36])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)N(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 15.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 250 ml. of hexamethylphosphoric acid triamide is treated under nitrogen at 5° C. with 0.055 mol. of sodium hydride (2.5 g. of a 55% dispersion in mineral oil) and then stirred at the same temperature for 15 minutes. At 5°-10° C. a solution of 15 g. of N,N-diethylchloroacetamide in 40 ml. of ethanol is added thereto and the mixture stirred for 30 minutes at room temperature and subsequently heated for 4 hours at 80° C. The mixture is cooled and poured into 2.5 liters of ice-water. After the addition of 150 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The aqueous layer is separated, the organic phase dried over sodium sulfate, filtered and evaporated to dryness. The residue is triturated with 100 ml. of ether, the unreacted starting material crystallizes out. The latter is removed by filtration under vacuum and washed with ether. The ethereal filtrate is evaporated to dryness. The oily residue is cooled and triturated with ether, crystals being obtained. Recrystallization from ethanol yields 5-chloro-2-[(diethylcarbamoyl)methyl]-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 118°-120° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:24][C:25]([F:42])([F:41])[C:26]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=2[N:27]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)CCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([N:30]1[CH2:29][C:28]2[N:27]=[C:26]([C:25]([F:42])([F:41])[F:24])[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]=2[CH2:32][CH2:31]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CNCC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (intermediate 1) and ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (intermediate 27) were treated with EDC, HOBt and N,N-diisopropylethylamine according to the procedure described for Example 1, Step A to afford the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[C:27]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CN(C)c1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-(dimethylamino)phenyl boronic acid according to the procedure described in example 21. MS m/z 280; HRMS: calcd for C19H21NO+H+, 280.16959; found (ESI, [M+H]+), 280.1689.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:47]([N+:51]1[N:55]=[C:54]([CH3:56])[S:53][C:52]=1[CH3:57])[CH2:48][CH2:49][CH3:50]>>[CH2:47]([N:51]1[N:55]=[C:54]([CH3:56])[S:53]/[C:52]/1=[CH:57]\[C:6]([C:5]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:8])[CH2:48][CH2:49][CH3:50]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-methoxy-4-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89-0.94 (m, 3 H) 1.29-1.37 (m, 2 H) 1.71-1.79 (m, 2 H) 2.20 (s, 3 H) 2.48 (s, 3H) 3.85 (s, 3 H) 4.23 (t, 2 H) 6.67 (s, 1 H) 7.22 (d, 1 H) 7.48 (s, 1 H) 7.53 (d, 1 H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([OH:23])[C:21]2[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-2-indolinone and 4-methyl-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and final purification by column chromatography on silica gel with CH2Cl2 as eluant.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4]([NH2:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[CH2:16]([C:18]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21])[CH3:17]>>[CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4]([NH:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:18]=2[CH2:16][CH3:17])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC1CN(C)CC(N)(c2ccccc2)C1
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCc1cc(C(F)(F)F)ccc1C(=O)NC1(c2ccccc2)CC(C)CN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 1, the title compound was prepared from (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidin-3-ylamine (Example A.20) and 2-Ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8). MS (m/e): 405.4 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].N1CCC[C@H]1C(O)=O.CCOC(C)=O>CS(C)=O.[Cu]I>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[CH3:23])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1ccccc1CN
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NCc2ccccc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (50 mg, 0.13 mmol) in DMSO (5 mL) (1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) was prepared as described for Compound 1 above). To this was added 2-methyl-benzylamine (40 mg, 0.33 mmol) followed by CuI (10 mg, 0.05 mmol). To the mixture was added L-proline (20 mg, 0.17 mmol). The resulting solution was held at 50° C. for 1 hr while the reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction mixture was allowed to cool to room temperature, then washed twice with H2O (30 mL each). After removal of the volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system. This resulted in 25 mg (44%) of the product [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:21]([Cl:20])=[O:23])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Solvent: ClCCl
Product: O=C(Cl)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 54F (73 mg, 0.28 mmol) in dichloromethane (2.5 mL) was added triphosgene (32 mg, 0.106 mmol), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with dichloromethane (10 mL) and washed by 10% aqueous NaHCO3 solution (5 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)=[C:40]([C:43]([OH:45])=O)[NH:41][N:42]=2)[CH:37]=1)[CH3:31].[C:56]([NH:63][CH2:64][CH2:65][CH2:66][NH2:67])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C(Cl)Cl>[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)=[C:40]([C:43]([NH:67][CH2:66][CH2:65][CH2:64][NH:63][C:56](=[O:57])[O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:45])[NH:41][N:42]=2)[CH:37]=1)[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCc1cc(-c2n[nH]c(C(=O)O)c2-c2ccc(OC)cc2)c(O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCc1cc(-c2n[nH]c(C(=O)NCCCNC(=O)OC(C)(C)C)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
HOBT (572 mg, 4.2 mmol), NMM (1.55 ml, 14.1 mmol) and EDAC.HCl (820 mg, 4.3 mmol) were added at 0° C. consecutively to a solution of 5-(5-ethyl-2,4-dihydroxy-phenyl)-4-(4-methoxyphenyl)-2H-pyrazole-3-carboxylic acid (500 mg, 1.4 mmol) in 40 ml of dry DCM. The resulting mixture was stirred at 0° C. for 15 minutes. Then a solution of N—BOC-1,3-diaminopropane (740 mg, 4.3 mmol) in 5 ml of dry DCM was added. The resulting mixture was stirred at 0° C. for one our and at room temperature for 2.5 hours. The reaction mixture was washed with 50 ml of 10% w/v aqueous citric acid solution, 50 ml 20% aqueous KHCO3 solution and 50 ml of distilled water. The organic extracts were dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by automated column chromatography on a 40 g RediSep™ normal phase silica cartridge using an ISCO Companion™ eluting with a mixture of 5% methanol in DCM was used. The fractions containing the desired product were combined and evaporated under reduced pressure go give the title compound as a white solid (450 mg, 63%); 1H NMR Spectrum: δH (400 MHz, DMSO-d6) 0.90 (3H t, J=7.5 Hz), 1.38 (9H, s), 1.56 (2H t, J=6.9 Hz), 2.28 (2H q, J=7.4 Hz), 2.95 (2H d, J=6.1 Hz), 3.15-3.20 (2H, m), 3.72 (3H, s), 6.41 (1H, s), 6.57 (2H, s), 6.72 (1H, s br), 6.78 (2H d, J=7.3 Hz), 7.12-7.14 (2H, m), 7.92-8.02 (1H, m br), 9.28-9.35 (2H, m), 12.89 (1H, s, br);
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[Cl-]>C(Cl)Cl>[CH2:5]([C@@H:2]1[CH2:3][O:4][C:17](=[O:19])[NH:1]1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H]1COC(=O)N1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 264.9 %

Procedure:
To a cooled (4° C.) solution of (R)-2-amino-4-methylpentan-1-ol (2.98 g, 25.4 mmol) and triethylamine (7.6 mL, 54 mmol, 2.1 equiv) in CH2Cl2 (80 mL) was added dropwise a solution of triphosgene (2.52 g, 8.49 mmol, 0.334 equiv) in 10 ml of CH2Cl2 over 30 min. The reaction mixture was stirred at 4° C. for 15 min, warmed up to room temperature and stirred for an additional 1 h. The mixture was treated with saturated NH4Cl (25 mL), followed by CH2Cl2 (50 mL) and the resulting mixture was stirred for 20 min. The layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (R)-4-isobutyloxazolidin-2-one (3.22 g) in 88% yield. The crude product was used for the next reaction without purification. 1H NMR (400 MHz, CD3OD) δ 4.53-4.47 (m, 1H), 4.00-3.92 (m, 2H), 1.67 (ddq, J=13, 8.0, 6.5 Hz, 1H), 1.56-1.48 (m, 1H), 1.40-1.32 (m, 1H), 0.95 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[NH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]#[N:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]([CH2:31][CH2:30][O:29][CH2:28][CH2:27][NH:26][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])#[N:33]
Reactant: N#CCCOCCN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCC#N)ccc21
Yield: 67.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-cyano-ethoxy)-ethyl]-amide (60 mg) was prepared by following General Procedure F starting 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 3-(2-amino-ethoxy)-propionitrile hydrochloride (100 mg), HBTU (85 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 456.0.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.8 g), anhydrous acetonitrile (18 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 3; 1.81 g) and DBU (0.90 g) was refluxed for an hour. The resulting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (25 ml) and, after cooling, the resulting precipitate was collected by filtration. Then this precipitate was suspended in methanol (18 ml), to this solution was added concentrated hydrochloric acid (18 ml) dropwise and stirred at room temperature for 15 minutes. The reacting mixture was neutralized with concentrated aqueous ammonia, after cooling, the resulting precipitate was collected by filtration and washed with water, methanol and ether successively to give the title compound (1.67 g) as white powder, mp 240°-243° C. (decompd.).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>CN(C=O)C>[OH:68][C@@H:67]([CH3:69])[C:66]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:70]
Reactant: C[C@H](O)C(=O)O
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in DMF (5 mL). N-Ethyldiisopropylamine (0.081 mL, 0.47 mmol) was added followed by O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and L-lactic acid (21.02 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the crude dissolved in MeOH and acetonitrile, filtered and purified by preparative HPLC yielding (S)-2-hydroxy-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propan-1-one (30.0 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[N+:20]([CH3:23])([O-:22])=[O:21]>O>[Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])([CH2:23][N+:20]([O-:22])=[O:21])[C:6]1=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=O)N(Cc2ccccc2Br)c2ccccc21
Solvent: O
Product: O=C1N(Cc2ccccc2Br)c2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 30 h

Procedure:
1-(2-bromobenzyl)indoline-2,3-dione (0.158 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 30 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=2[OH:13])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][O:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=1[C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:5])[CH3:21]
Reactant: O=C(c1c(O)cccc1O)C1CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(O)c1C(=O)C1CC1

Procedure:
To a mixture of cyclopropyl-(2,6-dihydroxy-phenyl)-methanone (398 mg) and potassium carbonate (500 mg) in acetone (5 ml) was added bromoacetic acid ethyl ester (300 μl) at room temperature. The suspension was heated to reflux for 1.5 hours and diluted with ethyl acetate (10 ml), washed with diluted hydrochloric acid (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified by silica gel column chromatography developed by hexane-ethyl acetate to give (2-cyclopropanecarbonyl-3-hydroxy-phenoxy)-acetic acid ethyl ester as a pale yellow solid (382 mg). EI-MS: m/z 264 (M+); 1H-NMR (CDCl3): δ 1.04-1.09 (2H, m), 1.23-1.29 (2H, m), 1.28 (3H, t, J=7.26 Hz), 2.26-2.35 (1H, m), 4.29 (2H, q, J=7.26 Hz), 4.70 (2H, s), 6.27 (1H, dd J=0.99 Hz, 8.25 Hz), 6.62 (1H, dd, J=0.99 Hz, 8.25 Hz), 6.41 (2H, d, J=8.25 Hz), 7.31 (1H, dd, J=8.25 Hz, 8.25 Hz), 12.89 (1H, s).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[C:3]1[C:12]([O:14]CC)=O.C(O[C:20](OCC)([CH3:23])[C:21]#[N:22])C.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[N:1][N:2]2[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[C:3]2[C:12]=1[OH:14])#[N:22]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(N)c1
Reactant: CCOC(C)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Temperature: 125 °C
Yield: 50 %

Procedure:
To a round bottom flask was added diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (40 g, 177 mmol), diethoxypropionitrile (53 mL) and p-TSA (10 g, 0.052 mmol). The reaction was heated at 125° C. for 3 hours and the EtOH was removed. The reaction was cooled to room temperature before DBU (30 g, 340 mmol) was added. The reaction was then heated at 80° C. for 2 hours. The reaction was cooled to room temperature and diluted with CH2Cl2. The mixture was washed with 5% citric acid solution (2×), water and brine solution. The organic layer was concentrated and the residue was purified by flash silica gel column chromatography (10% MeOH in CHCl3) to yield 20 g (50%) of the title compound as a brown oil. LCMS (condition A): m/z=230.2 −ve. H1 NMR (400 MHz, CDCl3) δ ppm: 9.53 (1H, br s), 8.32 (1H, s), 7.75 (1H, s), 6.75 (1H, s), 4.25 (2H, q), 1.28 (3H, t).
Reaction SMILES: Br[C:2]1C=COC=1C(O)=O.C(O)C.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([OH:26])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([O:26][CH3:2])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(O)c1occc1Br
Reactant: COc1ccc(C(=O)O)cc1NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(OC)c(NC(=O)OC(C)(C)C)c1

Procedure:
A reaction and treatment was conducted in the same manner as in Reference Example 1 except that the 3-bromo-2-furancarboxylic acid and ethanol used in Reference Example 1 were replaced with 3-(tert-butoxycarbonylamino)-4-methoxybenzoic acid (5.00 g) and methanol (0.76 ml), respectively, thereby giving 5.51 g of methyl 3-(tert-butoxycarbonylamino)-4-methoxybenzoate.