Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:27]([F:30])([F:29])[F:28].[OH-].[Na+]>CO.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:27]([F:30])([F:28])[F:29])[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
In a solution of 0.40 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-trifluoromethyl benzoic acid methyl ester in 5 ml of methanol, a solution of 0.10 g of sodium hydroxide in 2 ml of water was added, and stirred at room temperature for 18 hours. After the completion of the reaction, 10 ml of water was added in the reaction mixture, washed with 5 ml of toluene, aqueous phase was collected, adjusted to pH 1 to 2 with concentrated hydrochloric acid and then extracted with ethyl acetate (20 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.34 g of the aimed product as pale yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2N=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@H:58]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[CH2:59][NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([C@@H:43]([C:42](=[O:57])[N:41]([C@H:58]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[CH2:59][NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH3:40])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)[CH3:56])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1ccnc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (352 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). Hydroxy-7-azabenzotriazole (197 mg, 1.45 mmol) was added as a solid. The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (278 mg, 1.45 mmol) was added. The solution was stirred for 15 min at 0° C. A solution of N-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide (598 mg, 1.32 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine (0.23 ml, 1.32 mmol) were added successively. The solution was stirred for 18 h, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and extracted with 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (2:1) as eluent to give 740 mg of (3E)-4-(N-((1R)-1-(N-((1R)-1-benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=CC=CC=[C:2]12.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2>CC(C)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:1](=[O:11])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CC(C)=O
Product: O=C(O)CCC(=O)Nc1ccc2[nH]ncc2c1
Yield: 102.2 %

Procedure:
Phthalic anhydride (827 mg, 8.26 mmol) was added to a solution of 5-aminoindazole (1.0 g, 7.51 mmol) in acetone (60 ml) at room temperature, and the resulting mixture was refluxed for 4 hours. The solid precipitated was collected by filtration and dried under reduced pressure to obtain 4-(1H-indazol-5-ylamino)-4-oxobutanoic acid (1.79 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:4]=2[C:5]2[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[CH3:18][N:15]1[CH2:16][CH2:17][C:3]2[C:2]([NH:1][C:19](=[O:21])[CH3:20])=[CH:11][C:10]3[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6][C:5]=3[C:4]=2[CH2:14]1
Reactant: CN1CCc2c(N)cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2[nH]c(=O)c(=O)[nH]c2c2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from Example 79 (0.27 g, 1.1 mmol) in 25 mL acetic acid and 10 mL acetic anhydride was stirred at room temperature for 18 hours. After removing the solvent, the residue was washed with ether, dissolved in water and then basified with saturated sodium bicarbonate. The flask was cooled in the freezer for 2 hours and the precipitate collected by filtration, washed consecutively with water and ether, and dried over P2O5 in vacuo to give the title compound (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27](Cl)=[O:28])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:24]3[CH:23]=[C:22]([CH3:21])[O:26][N:25]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cc(C)on2)CC1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol from Example 47, Step 1) was combined with 5-methylisoxazole-3-carbonyl chloride (0.023 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (0 to 5% methanol in dichloromethane) to give the desired product (32 mg, 77%). LCMS calculated for C20H20ClN4O3 (M+H)+: m/z=399.1; Found: 399.1.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]([NH:21][NH:22][C:23](=[O:43])[CH2:24][NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]([NH:21][NH:22][C:23](=[O:43])[CH2:24][NH2:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NNC(=O)CN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of 1.54 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-[N-(9-fluorenylmethyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in 20 ml of dichloromethane was treated with 1.0 ml of piperidine. The mixture was stirred for 1.5 hours at room temperature and evaporated. The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 0.83 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-]=[N+]=[N-].[Na+].C(N1C=CN=C1C#N)C1C=CC=CC=1.N=[N+]=[N-].[NH:38]1C=[N:41][N:40]=[N:39]1>CN(C)C=O.O>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[NH:41][N:40]=[N:39][N:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nnn[nH]1
Reactant: O=Cc1nccn1Cc1ccccc1
Agent: N#Cc1nccn1Cc1ccccc1
Agent: [Cl-]
Agent: [N-]=[N+]=N
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cn2ccnc2-c2nnn[nH]2)cc1
Reaction time: 20 h

Procedure:
Obtained by reacting 9.3 g (0.05 mol) of 1-benzyl-2-formylimidazole (see Liebigs Ann. Chem. 718 (1968) pp. 249-259) with 8.0 g (0.15 mol) of ammonium chloride and 9.8 g (0.15 mol) of sodium azide in 50 ml of dimethylformamide at 120°-130° C. The isolation of the 1-benzyl-2-cyanoimidazole intermediate (obtained by Schmidt-rearrangement) may be omitted, since this compound adds excess hydrazoic acid to the tetrazole in situ. After 20 hours, it is cooled, and 500 ml of water are added, the precipitate formed filtered off and recrystallised several times from dimethylformamide. M.p. 274°-275° C.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:8]([CH3:18])=[N:9][C:10]([C:14]([F:17])([F:16])[F:15])=[N:11][C:12]=1[CH3:13])=[O:6]>CCO.O>[CH3:13][C:12]1[C:7]([C:5]([OH:6])=[O:4])=[C:8]([CH3:18])[N:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: COC(=O)c1c(C)nc(C(F)(F)F)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C(F)(F)F)nc(C)c1C(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
step B—A solution of KOH (1.74 g, 31.01 mmol) and water (10 mL) was added at RT to a solution of 4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (2.42 g, 10.33 mmol) in EtOH (20 mL). The resulting mixture was stirred at 40° C. overnight then cooled to RT and evaporated. The residue was partitioned between EtOAc and water. The aqueous layer was evaporated and the residue was taken up in H2O (1 mL). Concentrated HCl was added dropwise until crystals started to form. The mixture was diluted with H2O (5 mL) and stored in a refrigerator overnight. The crystals were filtered, rinsed with ice-cold water then ice-cold Et2O, and dried to afford 1.5 g (66%) of 4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>O1CCOCC1>[ClH:32].[ClH:32].[ClH:32].[C:26]1([CH:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[CH2:25][CH2:24]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCC(c4ccccc4)CC3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(C2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.83 h

Procedure:
To a solution of 4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (2.45 g) in 1,4-dioxane (62 ml) was added dropwise 4N-HCl/1,4-dioxane (58 ml) at ambient temperature. The reaction mixture was stirred for 110 minutes at ambient temperature, and stirred for 2 hours at 80° C. The precipitate was filtered and dried to give 1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine trihydrochloride salt (2.07 g).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2-Bromo-6-chloro-4-(trifluoromethyl)benzaldehyde (3.4 g, 11.9 mmol) (as described in Example 72, STEP C), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (5.0 g, 14.3 mmol), Pd(dppf)Cl2 (435 mg, 0.6 mmol), and 2 M K2CO3 (aq) (11.9 mL, 23.8 mmol) were dissolved in 1,4-dioxane (48 mL) and heated to 90° C. After 2 h the temperature was lowered to 80° C. After 14 h the resulting mixture was concentrated, diluted with EtOAc and 4M aqueous NaCl, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:24][C:25]5[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=5)=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: Cc1cccc(CBr)c1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(C)c5)o4)cc23)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-methylbenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].CC([N:23]([CH:27]1[CH2:30][NH:29][CH2:28]1)C(=O)[O-])(C)C.C(N(CC)CC)C>C(#N)C>[NH2:23][CH:27]1[CH2:30][N:29]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(C)(C)N(C(=O)[O-])C1CNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(N)C3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A suspension of 0.81 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.0 g (6.0 mmole) of 1,1-dimethylethyl-(3-azetidinyl)carbamate, 1.0 g (10 mmole) triethylamine and 50 ml of acetonitrile was heated at reflux 35 for four hours. The solvent was removed in vacuo and the residue was dissolved in 10 ml of trifluoroacetic acid. The solution was stirred at room temperature for one hour, the solvent was removed in vacuo and the residue dissolved in water. The turbid solution was clarified by filtration and the filtrate adjusted to pH 7.3 with 1.0N sodium hydroxide. The resulting precipitate was removed by filtration, washed successively with water, ethanol and ether. Drying in vacuo gave 0.2 g of 7-(3-amino-1-azetidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 260°-262° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]([O:9][CH2:10][CH:11]1[O:16][CH2:15][C:14]2[S:17][C:18]([NH2:27])=[C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]=2[CH2:12]1)=[O:8])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:5][C:6](=[O:28])[C:7]([O:9][CH2:10][CH:11]1[O:16][CH2:15][C:14]2[S:17][C:18]([NH2:27])=[C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C:13]=2[CH2:12]1)=[O:8]
Reactant: CC(C)(C)OC(=O)C(=O)OCC1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=O)OCC1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Yield: 8.7 %

Procedure:
A solution of the above oxalic acid 2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester tert-butyl ester (8.3 g, 20.1 mmol) and potassium carbonate (1.7 g, 12.3 mmol) was stirred in methanol (80 ml) in presence of water (3 ml) at room temperature for 10 min., at which time TLC indicated reaction complete. Methanol was removed in vacuo and the crude product was dissolved in dichloromethane (300 ml) and washed with water (3×150 ml). The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified on flash chromatography on silica gel using a gradient of hexane/ethyl acetate (90:10 to 50:50 gradient) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 0.65 g (9%) of oxalic acid 2-amino-3-tert-butoxycarbonyl-4,7-dihydro-5H-thieno[2,3-c]pyran-5-ylmethyl ester methyl ester as a solid.
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]1=[NH:18].[CH3:19][C:20]1([CH3:28])[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]1=[N:18][C:25]([CH:21]1[C:22]([CH3:24])([CH3:23])[C:20]1([CH3:28])[CH3:19])=[O:26]
Reactant: COCCn1c(-c2ccccc2)c(C)sc1=N
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c(-c2ccccc2)c(C)sc1=NC(=O)C1C(C)(C)C1(C)C

Procedure:
A mixture of the product of Example 119A (290 mg, 1.16 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (182 mg, 1.28 mmol), HATU (661 mg, 1.74 mmol) and triethylamine (0.97 mL, 6.96 mmol) in 15 mL of DMF was processed according to the method of Example 2B to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.17 (s, 6H) 1.26 (s, 6H) 1.49 (s, 1H) 2.01 (s, 3H) 3.02 (s, 3H) 3.43 (t, J=6.0 Hz, 2H) 4.06 (t, J=5.8 Hz, 2H) 7.39-7.43 (m, 2H) 7.50-7.57 (m, 3H); MS (DCI/NH3) m/z 373 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH2:18][CH2:19][CH3:20])([NH:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:11])[CH2:6][CH2:7][CH3:8])C.Cl>[OH-].[Na+]>[CH2:6]([C:5]([NH:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:11])([CH2:18][CH2:19][CH3:20])[C:4]([OH:21])=[O:3])[CH2:7][CH3:8]
Reactant: CCCC(CCC)(NC(=O)Nc1nccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CCC)(NC(=O)Nc1nccs1)C(=O)O
Yield: 92.9 %

Procedure:
10.03 g of the product from stage 4 were dissolved with stirring in 200 ml of semi-concentrated sodium hydroxide solution at a temperature of 20° C. The pH was then adjusted to 4 with concentrated hydrochloric acid and extracted three times with 50 ml portions of dichloromethane. The extracts were washed once with a saturated sodium chloride solution and dried over sodium sulphate. Once the solvent had been removed by distillation, 8.48 g of 2-propyl-2-(3-thiazol-2-ylureido)pentanoic acid (93% of th.) were obtained in the form of white crystals (mp 154-155° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:24][C:23]([CH3:25])([CH3:26])[C:22]([C:12]1[C:11]([CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:41]3[CH:40]=[N:39][C:38]([O:37][CH3:36])=[CH:43][CH:42]=3)[CH:3]=2)=[O:9])[N:18]2[C:13]=1[CH:14]=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:17]2)=[O:27]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(-c2ccc(OC)nc2)c1
Temperature: 23 °C
Yield: 24.7 %

Procedure:
A solution of methyl 3-{3-[(3-bromophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.185 mmol), 2-(methoxy)pyridine-5-boronic acid (42.5 mg, 0.278 mmol), tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.019 mmol) in THF (2.0 mL) and aqueous 20% Na2CO3 (1.0 mL) is heated at 70° C. for 1 h. The mixture is cooled to 23° C. and partitioned between Et2O and water. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 30% EtOAc in hexanes) gives methyl 3-[1-(2,2-dimethylpropanoyl)-3-{[3-(6-methoxypyridin-3-yl)phenyl]carbonyl}-7-(propan-2-yl)indolizin-2-yl]-2,2-dimethylpropanoate (26 mg, 25%) which is dissolved in MeOH (1.5 mL), and 6M aqueous NaOH (1.5 mL) and heated at 70° C. for 1 h. The mixture is then cooled to 23° C., acidified to pH=1 with concentrated aqueous HCl, and partitioned between CH2Cl2 and brine. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give the title compound (20 mg, 79%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:16]([N:8]([CH2:6][CH2:5][CH2:4][CH2:10][CH3:9])[C:7]1[CH:9]=[CH:10][C:4]([Br:3])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)c1ccc(Br)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium hydride (480 mg, 1.5 eq.) was added to a solution of 4-bromo-3-trifluoromethylaniline (1.92 g, 5 mmol) and 1-bromopentane (3 mL, 3 eq.) in dimethylformamide (10 mL) at 0° C. After 1 hour a further (320 mg, 1 eq.) of sodium hydride was added and the reaction was left overnight. The reaction was heated to 50° C. and left overnight. The reaction was quenched with methanol and partitioned between water and petroleum ether. The organic extract was concentrated under reduced pressure and the residue was purified via flash column chromatography using petroleum ether as eluent to give N,N-Dipentyl-4-bromo-3-trifluoromethylaniline (3) (2.84 g. 93%). 1H NMIR (CDCl3) 6 7.34 (d, IH, ArH); 6.80 (d, 1H, ArH); 6.52 (dd, 1H, ArH); 3.18 (t, 4H, 2×NCH2); 0.86 (t, 6H, CH˜1b). TLC (silica gel): RI˜0.55 (petroleum ether).