Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[OH:20])[CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:7]=1[CH3:16].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(O)C.O1CCCC1>[CH2:21]([NH:23][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[OH:20])[CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:7]=1[CH3:16])[CH3:22]
Reactant: Cc1ccn2c(Cc3ccc(O)c(N)c3)c(C)nc2c1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCNC(=O)Nc1cc(Cc2c(C)nc3cc(C)ccn23)ccc1O
Yield: 94.3 %

Procedure:
A solution of 3-(3-amino-4-hydroxybenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (3.1 g) and ethyl isocyanate (1.24 g) in ethanol (50 ml) and tetrahydrofuran (50 ml) was refluxed for 2.5 hours under stirring. The reaction mixture was concentrated in vacuo and the precipitate was collected by filtration to give 3-[3-(3-ethylureido)-4-hydroxybenzyl]-2,7-dimethylimidazo[1,2-a]pyridine (3.7 g).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>C(Cl)Cl>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][N:22]2[C:23]([CH2:25][CH2:26][OH:27])=[CH:24][N:20]=[CH:21]2)=[CH:40][CH:41]=1
Reactant: Fc1ccc(-c2ccccc2CBr)cc1
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: ClCCl
Product: OCCc1cncn1Cc1ccccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(1-trityl-1H-imidazol-4-yl)ethanol (0.65 g, 1.80 mmol), acetonitrile (9 mL) and CH2Cl2 (12 mL) is added a solution of 2-bromomethyl-4′-fluorobiphenyl (0.478 g, 1.80 mmol) in CH2Cl2 (2 mL). The resulting mixture is stirred at room temperature overnight. The solution is concentrated and the residue is taken up in MeOH and heated to 75° C. for 3.5 h. The solution is then concentrated and the residue is partitioned between CH2Cl2 and aqueous 5% NaHCO3. The aqueous layer is then extracted with CH2Cl2 (3×). The combined organic layers are then washed with brine and dried over Na2SO4. The residue is then purified by flash chromatography (CH2Cl2/MeOH) give 2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol. MS (ESI) m/z 297.1 (M+H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:7]\[CH2:8][CH3:9])/[CH:3]=[CH:4]/[CH2:5][OH:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:6][CH2:5]/[CH:4]=[CH:3]/[C:2](/[CH3:1])=[CH:7]/[CH2:8][CH3:9])(=[O:12])[CH3:11]
Reactant: CC/C=C(C)/C=C/CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC/C=C(C)/C=C/COC(C)=O
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of (E,E)-4-methyl-2,4-heptadien-1-ol (106 g) in pyridine (333 g) at 0° C. was added dropwise acetic anhydride (258 g). After two hours at room temperature, the reaction mixture was evaporated in vacuo. The residue was diluted with ethyl acetate, washed with 0.5N-hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was distilled to give (E,E)-1-acetoxy-4-methyl-2,4-heptadiene (117.65 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:20]3[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)[CH2:22][CH2:21]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCCN1CCN(CCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(NCCCN3CCN(CCCNc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1

Procedure:
A solution of 4,7-dichloroquinoline (1.58 g, 8.0 mmol) and 1,4-bis(3-aminopropyl)piperazine (0.33 mL, 1.6 mmol) in DMF (5 mL) is refluxed (160° C.) for 18 h in the presence of K2CO3 (1.77 g, 12.8 mmol). After evaporation, the media is diluted with HCl 1M, and washed with ethyl acetate. Aqueous layer is alcalinised with NaHCO3, extracted with CH2Cl2, and dried over MgSO4. Crude compound is purified by precipitation in ethyl acetate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3cccc(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 437 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[CH2:50]([CH2:52][NH2:53])[OH:51]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:53][CH2:52][CH2:50][OH:51])=[O:27])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: O=C(O)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
100 mg (0.2 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, 73 mg (0.38 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 44 mg (0.38 mmol) of N-hydroxysuccinimide are dissolved in 3 ml of dimethyflormamide and stirred for 2.5 h at RT. The reaction mixture is then added dropwise at 0° over a period of 30 minutes to a solution of 0.75 ml (12.3 mmol) of ethanolamine in 2 ml of DMF. After stirring for 14 h at RT, the reaction mixture is poured into 50 ml of ethyl acetate and extracted with aqueous sodium chloride solution (30 ml) and pH 7 buffer (30 ml), and the organic phase is dried (sodium sulfate) and concentrated. Crystallisation from THF/diethyl ether gives N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-hydroxy-ethyl-aminocarbonyl)-4-pyridyl]-2-pyrimidineamine; m.p. 159°, FAB-MS: 452 (M+ +H).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>N.CC(O)C>[CH:18]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: N
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccccc3)c12
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccccc3)c12
Temperature: 110 °C
Yield: 70 %

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of 8-chloro-3-cyclobutyl-1-phenylimidazo[1,5-a]pyrazine (602.9 mg, 2.125 mmol) in NH3/i-PrOH (2M, 15 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 2 d. After excess NH3/i-PrOH was removed in vacuo, the residue was extracted with CH2Cl2 (3×30 mL), and the combined organic layers were washed with brine (3×30 mL), dried over anhydrous MgSO4, filtered, and concentrated. The material obtained (670 mg) was recrystallized from EtOAc, granting 393.3 mg (70%, 1.488 mmol) of the title compound, as pale pink crystals. The mother liquor was reduced ca. 50% in vacuo and again recrystallized from EtOAc, affording an additional 38.4 mg (7%, 0.145 mmol) of the title compound, as pink crystals, >99% pure by HPLC; mp. 164-166° C.; 1H NMR (CDCl3, 400 MHz) δ 1.98-2.09 (m, 1H), 2.11-2.23 (m, 1H), 2.44-2.54 (m, 2H), 2.58-2.70 (m, 2H), 3.82 (quint, J=8.4 Hz, 1H), 5.02 (s, br, —NH2), 7.05 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.38-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.65-7.70 (m, 2H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ 18.87 (−), 26.94 (2C, −), 31.48 (+), 106.61 (+), 113.93 (Cquart), 127.43 (+), 128.08 (+), 128.81 (2C, +), 129.67 (2C, +), 134.87 (Cquart), 135.32 (Cquart), 143.90 (Cquart), 151.75 (Cquart). MS (ES+): m/z 265.2 (100) [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Temperature: 26 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed ethyl 2-(4-fluorophenyl)quinazoline-4-carboxylate (15 g, 50.63 mmol, 1.00 equiv), oxolane (150 mL), lithiumol (2.4 g, 100.22 mmol, 2.00 equiv) and water (50 mL). The resulting solution was stirred overnight at 26° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The solids were collected by filtration and washed with water. This resulted in 10 g (74%) of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.37-7.41 (m, 2H), 7.65-7.69 (m, 1H), 7.96-8.03 (m, 2H), 8.20-8.22 (m, 1H), 8.56-8.61 (m, 2H); MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([N+:20]([O-])=O)[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([NH2:20])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C([N+](=O)[O-])S1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N)S1
Yield: 89.9 %

Procedure:
10.4 g of the 2-chloro-4-fluoro-5-nitro-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P1 are hydrogenated with hydrogen under normal pressure in 150 ml of tetrahydrofuran at a temperature of 20°-25° C. in the presence of 2 g of Raney nickel catalyst. After the stoichiometric amount of hydrogen has been consumed, the catalyst is separated off and the solution is concentrated by evaporation, yielding 8.6 g of 5-amino-2-chloro-4-fluoro-thiolbenzoic acid (methoxycarbonylmethyl) ester having a melting point of from +88° to +89° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:24]Br>O>[Br:24][C:21]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[C:14]2[N:15]=[C:16]([NH2:23])[NH:17][C:18](=[O:22])[C:19]=2[N:20]=1
Reactant: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(N)nc21)OCC
Reactant: BrBr
Solvent: O
Product: CCOP(=O)(COCCn1c(Br)nc2c(=O)[nH]c(N)nc21)OCC
Reaction time: 1 h

Procedure:
9-(2'-(diethylphosphonomethoxy)ethyl)guanine (0.360 g, 1.04 mmol) was then dissolved in 10 ml H2O and treated dropwise with the aqueous bromine solution until the color of Br2 persisted. The reaction mixture was allowed to stand at 0° C. for 1 h and then was concentrated to afford a dark yellow viscous gum. Purification was accomplished by column chromatography on silica gel (MeOH--CH2Cl2) to provide 0.31 g of 8-bromo-9-(2'-(diethylphosphonomethoxy)ethyl)guanine as an orange powder.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:5]=2[CH:4]=[N:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2C1CCNCC1
Temperature: 45 °C
Reaction time: 21 h
Yield: 46.4 %

Procedure:
To a solution of tert-butyl 4-(1,7-dimethyl-9-oxo-1,9-dihydro-4H-pyrazolo[4,3-b]quinolin-4-yl)-1-piperidinecarboxylate (EXAMPLE 64, step 1, 62 mg, 0.16 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (0.03 ml, 0.39 mmol) and the mixture was stirred at room temperature for 7 h and at 45° C. for 21 h. After evaporation, the residue was dissolved in dichloromethane (20 ml), washed with saturated aqueous sodium bicarbonate (20 ml) and dried over sodium sulfate. Removal of solvent gave 22 mg (47%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5]1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:7][N:6]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:5]1)#[N:2]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
tert-Butyl (3R,5S)-3-carbamoyl-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate (1.01 g) was dissolved in pyridine (10 ml), trifluoroacetic anhydride (570 μl) was added at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate. 1M Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate was concentrated under reduced pressure to give the object product (1.01 g).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=1.C(Cl)(C([Cl:20])=O)=O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([C:13]([Cl:20])=[O:15])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A drop of DMF was added to a stirred solution of 6-chloropyrimidine-4-carboxylic acid (5.5 g, 34.7 mmol) and (COCl)2 (12 mL) in DCM (100 mL). The mixture was stirred at 25° C. for 2 h. The solvent was evaporated under reduced pressure to give crude 6-chloropyrimidine-4-carbonyl chloride (6.0 g, yield: 97.7%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H][H]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2
Reactant: [H][H]
Reactant: Cc1ccc(O)c2ccc(=O)[nH]c12
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(O)c2c1NC(=O)CC2
Yield: 99.9 %

Procedure:
5-Hydroxy-8-methylcarbostyril (20.0 g, 0.114M) was dissolved in acetic acid (800 ml). To the solution, 10% palladium-on-carbon (10.0 g) was added. The mixture was stirred at 80° C. for 4 hours in the stream of hydrogen. The reaction mixture was filtered, and the filtrate was distilled off under reduced pressure. The residue was extracted from a mixture of chloroform-methanol (10:1) and saturated aqueous sodium bicarbonate solution. The organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The resultant residue was recrystallized from methanol-ether to obtain 20.2 g of the title compound as pale yellow powdery crystals (99.9%).
Reaction SMILES: [CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]1([C:54](Cl)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>N1C=CC=CC=1>[CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][O:43][C:54]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](CO)O[C@@]1(O)Cc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@@]1(O)Cc1ccccc1
Yield: 82 %

Procedure:
A solution of 0.66 g of benzyl (benzyl 2-acetamido-2-deoxy-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutaminate (12A, n = 2, X1 = L-alanyl, R2 = CH3) and 0.56 g of triphenylmethyl chloride in 10 ml of pyridine is stirred at 22° C for 5 days and is then evaporated to dryness in vacuo. The residue is partitioned between 30 ml of chloroform and 30 ml of water, the chloroform phase is extracted twice more with 30 ml of water, dried over magnesium sulfate, concentrated in vacuo and the residue is triturated with 50 ml of ether. The resulting solid is collected by filtration, washed with ether and dried giving 0.74 g of benzyl (benzyl 2-acetamido-2-deoxy-6-O-triphenylmethyl-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutaminate (12B, n = 2, X1 = L-alanyl, R2 = CH3).
Reaction SMILES: [CH2:1]([N:4]([CH:21]1[CH:24]([C:25]([O-:27])=[O:26])[CH:23]([C:28]([O-:30])=[O:29])[CH2:22]1)[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6])[CH2:2][CH3:3].[OH-].[Na+]>>[CH2:1]([N:4]([CH:21]1[CH:24]([C:25]([OH:27])=[O:26])[CH:23]([C:28]([OH:30])=[O:29])[CH2:22]1)[C:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(C(=O)Cc1ccc(Oc2ccccc2)cc1)C1CC(C(=O)[O-])C1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCN(C(=O)Cc1ccc(Oc2ccccc2)cc1)C1CC(C(=O)O)C1C(=O)O

Procedure:
The compound resulting from Example 124A is reacted with propionyl chloride in the presence of triethylamine to give methyl 1,2-di(propionylamino)cyclobutane-3,4-dicarboxylate. Reduction of the diamide with borane-tetrahydrofuran complex at 0° C. affords methyl 1,2-di(n-propylamino)cyclobutane-3,4-dicarboxylate. Treatment of this secondary amine with the acid chloride of 4-phenoxyphenylacetic acid in the presence of triethylamine yields methyl1,2-di[(N-propyl-N-(4-phenoxybenzyl)carbonylamino]cyclobutane-3,4-dicarboxylate. Hydrolysis of the methyl esters with aqueous sodium hydroxide affords the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[C:10]([N+:25]([O-])=O)=[C:9]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:8]=2)[CH:4]=[N:3]1>CO.[Pd]>[NH2:25][C:10]1[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[N:12][C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:8][C:9]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: Cn1cc(-c2cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c(NCc3ccc4ncccc4c3)n2)cn1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(-c2cc(NC(=O)OC(C)(C)C)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate (950 mg, 2 mmol) in methanol (10 mL) was added 10% Pd/C (95 mg, 0.1 eq). The reaction was stirred at room temperature under 1 atm of H2 for 1 h, then filtered. The filtrate was concentrated to afford the title compound (890 mg), which was used for the next step without further purification. MS (m/z): 446 (M+1)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([C:1]2([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCCO1
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
To a solution of delta-valerolactone (1.854 mL, 19.98 mmol) in THF (20 mL) was added 1M phenylmagnesium bromide (19.98 mL, 19.98 mmol) dropwise at room temperature (exothermic), and the mixture was stirred at room temperature for 5 hrs. Then the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 4:6 followed by 1:1 EtOAc-hexane to give 1.97 g of 2-phenyltetrahydro-2H-pyran-2-ol as oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.92-8.00 (1H, m), 7.17-7.60 (5H, m), 3.67 (1H, t, J=6.15 Hz), 3.03 (1H, t, J=7.14 Hz), 2.25-2.37 (1H, m), 1.75-1.92 (2H, m), 1.54-1.71 (2H, m), 1.30-1.43 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[C:3]=1[NH:20]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:20][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[CH:5]=2)[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2ccc(Br)c(N)c2c1
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-1-(tert-butoxycarbonylamino)-7-(tert-butyldimethylsilyloxy)naphthalene, as described above in Step G, (6.0 g, 13.26 mmol) in CH2Cl2 (100 mL) at 0° C. was added TFA (10 mL). After 45 min, the mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of hexane—5% to 20% CH2Cl2, to yield the above-titled product.