Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])C.O[Li].O.Cl>CCO.C1COCC1.O>[F:12][C:11]([F:13])([F:14])/[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:26])([CH3:27])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)=[CH:9]\[CH:8]=[CH:7]\[C:6](\[CH3:30])=[CH:5]\[C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F)=C\C(=O)O
Temperature: 40 °C

Procedure:
To a solution of (2E,4E,6Z)-8,8,8-trifluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Intermediate 5, 100 mg, 0.23 mmol) in EtOH-THF-H2O (2 mL, 2 mL, 0.3 mL) was added LiOH.H2O 29 mg, 0.69 mmol). The mixture was heated to 40° C. for 4 h and was cooled to ambient temperature, acidified with 1M HCl and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40% EtOAc-hexane) to give a 3:2 mixture of the title compound and its 13-Z isomer (91 mg). Further purification by HPLC (20% EtOAc-hexane) afforded the title compound as a white solid (39 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.Cl.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: Clc1ccncc1
Agent: Cl
Product: COc1ccc(Nc2ccncc2)c(C(=O)O)c1
Yield: 111.7 %

Procedure:
5-Methoxy-2-(4-pyridinylamino)benzoic acid was prepared from 4.9 g of 5-methoxyanthranilic acid and 4.4 g of 4-chloropyridine hydrochloride according to the procedure of Example 1, part (a). There was obtained 8.0 g of 5-methoxy-2-(4-pyridinylamino)benzoic acid which was recrystallized from water and used directly in the next reaction.
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:22])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=O.[Cl:23][C:24]1[C:25]([CH2:38][C:39]([NH2:41])=[O:40])=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:34][N:35]([CH3:37])[CH3:36].[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[Cl:23][C:24]1[C:25]([C:38]2[C:39](=[O:40])[NH:41][C:9](=[O:22])[C:10]=2[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:21])[CH:13]=2)=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:34][N:35]([CH3:36])[CH3:37]
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Reactant: CN(C)Cc1cccc2cc(Cl)c(CC(N)=O)cc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cccc2cc(Cl)c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.26 ml, 0.26 mmol, 3.0 equiv) was added at room temperature under an atmosphere of argon to a solution of (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (24 mg, 0.11 mmol, 1.3 equiv) and of crude 2-(3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetamide (24 mg) in anhydrous tetrahydrofuran (2.5 ml, dried over molecular sieves). The reaction mixture was stirred for 1 hour at room temperature. It was then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC afforded the title compound (4.9 mg, 4% for two steps) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=11.20 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 8.01-7.92 (m, 1H), 7.80-7.70 (m, 1H), 7.62-7.57 (m, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.00 (t, J=7.9 Hz, 1H), 6.45 (t, J=7.5 Hz, 1H), 6.23 (d, J=8.0 Hz, 1H), 4.85-4.65 (br d, 2H), 3.87 (s, 3H), 2.85 (br s, 3H), 2.76 (br s, 3H). MS (ES+): 444 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:23]([O:35][CH3:36])=[CH:24][C:25]2[N:31]([CH3:32])[C:30](=[O:33])[O:29][CH2:28][CH2:27][C:26]=2[CH:34]=1.C(O)(C)C>Cl.O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[C:23]([O:35][CH3:36])=[CH:24][C:25]3[N:31]([CH3:32])[C:30](=[O:33])[O:29][CH2:28][CH2:27][C:26]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCOC(=O)N2C
Yield: 37.7 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (60.0 mg, 0.177 mmol), 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (39.3 mg, 0.177 mmol) and 5 drops of HCl/dioxane were stirred in isopropyl alcohol (2.00 mL, 26.1 mmol) at 120° C. in a sealed tube. After 24 hours the reaction mixture was concentrated and then extracted with DCM (20 mL) and washed with sat. NaHCO3 (20 mL) followed by water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on ISCO flash system (0-10% DCM:MeOH) to obtain one peak by LC/MS. When analyzed by HPLC, two peaks were shown. The fractions were concentrated and the residue was chromatographed on ISCO flash system (0-100% Hex:EtOAc) to obtain the product and the decarboxylated side product. The product was isolated as a pale blue solid (35.0 mg, 37.7%). mp: 160-162° C., MS (ESI+): 525 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.15 (d, 1H), 7.01 (s, 1H), 6.85 (d, 1H), 4.36 (m, 2H), 3.88 (s, 3H), 3.30 (s, 3H), 2.90 (br s, 5H), 1.99 (br s, 3H), 1.7 (d, 2H), 1.5-1.1 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CC(C)(C)c1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)(C)C)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-tert-butylpyridine (Preparation is described in Example 69).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1)=[CH2:2].[H-].[Na+].I[CH3:17].O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:17])[C:10]2=[O:13])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CI
Reactant: C=Cc1ccc2c(c1)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2c(c1)C(=O)N(C)CC2
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of 7-ethenyl-3,4-dihydro-1(2H)-isoquinolinone (224 mg, 1.295 mmol) in toluene (2 ml) and tetrahydrofuran (2 ml) at 0° C. was added sodium hydride (60% in oil, 37 mg, 1.554 mmol). The reaction mixture was warmed to room temperature and stirred for 0.5 h before addition of iodomethane (242 μl, 3.885 mmol). The reaction mixture was stirred at room temperature for 1 h before addition of additional iodomethane (242 μl, 3.885 mmol). The reaction mixture was then stirred at room temperature for a further 1 h before addition of water (20 ml). The mixture was extracted with 10% methanol/dichloromethane (3×100 ml), the organic layers were dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (181 mg, 75%).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+].O>CCO.C(OCC)(=O)C.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:27])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9]3=[O:26])=[CH:14][CH:13]=2)=[N:18][CH:19]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O

Procedure:
The compound of example 391 (1.5 g, 0.0040 mol), iron (0.533 g, 0.0095 mol) and ammonium chloride (0.930 g, 0.0174 mol) in EtOH: H2O (22.5 mL, 15:7.5) was refluxed for about 16 h. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated to obtain a residue which was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain a residue, which was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [I-].[K+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH:4]([CH3:6])[CH3:5].[Br:17]Br>O>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[Br:17])[CH:4]([CH3:6])[CH3:5]
Reactant: BrBr
Reactant: CC(C)COc1ccc([N+](=O)[O-])cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)COc1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Subsequently, a catalytic amount of potassium iodide was added to 4-isobutoxynitrobenzene (203 g) and the mixture was heated to 60° C. Bromine (183 g) was added dropwise over 3 h. The mixture was stirred further for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 2-isobutoxy-5-nitrobromobenzene (248 g), boiling point: 135–140° C./0.25 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:29])[C:24](OCC)=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:30][NH2:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:29])[C:24]([NH:30][NH2:31])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)OCC
Solvent: CO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate (450 mg, 1.08 mmol) in MeOH (24 mL) is added a solution of 50% wt hydrazine (0.068 ml, 1.08 mmol) in MeOH (10 mL) at −20° C. After stirring for 18 hours at room temperature, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate (412 mg). HPLC retention time=1.76 minutes (condition A); MS (m+1)=404.1
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][S:14][CH2:15][CH2:16][CH2:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[F:24][C:18]([F:23])([C:19]([F:20])([F:21])[F:22])[CH2:17][CH2:16][CH2:15][S:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CSCCCC(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)CCCSC[C@@H]1CCCN1
Temperature: 0 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
2.55 g of N-tert-butyloxycarbonyl-(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidine is added to 5.4 ml of trifluoroacetic acid, cooled to 0°C., and the mixture is stirred for 1.5 hours at 0° C. and for 16 hours at room temperature. The reaction mixture is poured onto 10% sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 1.8 g of the title compound is obtained as oily crude product.
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=2)[CH:11]=1)[CH2:4][C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH3:36][C:34]([CH3:35])([CH3:37])[CH2:33][C:20]1[N:19]=[C:18]([CH2:17][O:16][C:12]2[CH:11]=[C:10]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]([OH:7])=[O:6])[CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32]
Reactant: CCOC(=O)CN(CC)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC(=O)O)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(ethyl(3-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)phenyl)amino)acetate (entire amount) in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (90 mg) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10]>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Solvent: CCO
Product: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Yield: 49.3 %

Procedure:
The compound of Example 1 (750 mg, 3.75 mmol) was dissolved in ethanol (4 ml) and the enantiomers were separated by automated preparative liquid chromatography (Gilson system, 50×50 mm ID Chiralcel OD, 20 μm column, 50 ml/min) using ethanol:hexane [10:90] as the mobile phase. The appropriate fractions were combined and concentrated to give the title compound (370 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mmol of 2-(4-((6-fluoro-2-quinolinyl)oxy)phenoxy)propionyl chloride, prepared using substantially the procedure of Step A of Example 1 from the corresponding acid in 5 milliliters (ml) of methylene chloride, was slowly added to an ice-cooled solution comprising 0.89 grams (g) (5.5 mmol) of 4-aminobenzotrifluoride and 0.61 g (6 mmol) of triethylamine in 30 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 2 hours. The mixture was poured into a dilute aqueous HCl solution. The organic layer was separated, washed with water, then washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was taken up in boiling methylcyclohexane, filtered and filtrate allowed to cool to give 1.68 g (71 percent of theoretical) of the above-named product as colorless crystals. The product melted at 153°-155° C. and its structure was confirmed by its infrared (IR) and its nuclear magnetic resonance (NMR) spectrum. (Compound 3)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[CH3:21][NH2:22].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH3:21])[C:12]=2[CH2:19][CH3:20])[CH:3]=1
Reactant: CN
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CCc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.39 g, 1.3 mmol) in ethanol (20 mL) was added methylamine (33% in ethanol, 5.0 mL, 40 mmol), and the reaction mixture stirred for 24 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (148 mg, 1.3 mmol) in methanol (5 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(2-ethyl-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (455 mg, 86%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH3:23])[CH:20]([CH2:24][CH3:25])[O:19]1>>[CH3:23][CH:21]1[CH:20]([CH2:24][CH3:25])[O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1
Reactant: COc1ccccc1N
Reactant: CCC1OC(CBr)OC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1OC(CNc2ccccc2OC)OC1C

Procedure:
2-Methoxyaniline (0.05 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-methyl-5-ethyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4-methyl-5-ethyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(CC)CC
Yield: 82.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 2.6 ml (0.025 mol) of diethylamine in 25 ml of DMF were reacted at room temperature for 16 hours affording a yellow semi-solid oil which was kugelrohr distilled at 80 Pa, pot temperature 102°-105° C., to give 4.63 g (82.3%) of product as a yellow solid; mp 31.5°-33° C.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[NH2:2].[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[O:18]=[C:17]1[N:1]([C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])[N:2]=[C:15]([CH2:14][CH2:12][CH3:13])[CH2:16]1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1ccccc1C(=O)O
Product: CCCC1=NN(c2ccccc2C(=O)O)C(=O)C1

Procedure:
From the reaction of 2-hydrazinobenzoic acid and ethylbutyrylacetate, 2-(4,5-dihydro- 5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yields 2-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid, Mp 126.9° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([N:15]3[CH2:19][C@@H:18]([F:20])[CH2:17][C@@H:16]3[C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[O:28][C@H:29]3[CH2:33][CH2:32][O:31][CH2:30]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.[Li+].[OH-]>C(O)C>[F:20][C@@H:18]1[CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]3[N:10]([C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=3)[CH:11]=2)[C@@H:16]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][C@H:29]2[CH2:33][CH2:32][O:31][CH2:30]2)[CH2:17]1
Reactant: CCOC(=O)c1cnc2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3O[C@H]3CCOC3)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2ccc(N3C[C@@H](F)C[C@@H]3c3cc(F)ccc3O[C@H]3CCOC3)cn12
Temperature: 85 °C
Reaction time: 5 h
Yield: 8.2 %

Procedure:
To a stirred solution of Ethyl-6-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (1.3 g, 28.43 mmol) in ethanol was added 1M LiOH (2.6 ml) solution and stirred for 5 h at 85° C. Solvent was removed under reduced pressure and residue was dissolved in water, extracted unwanted impurities with Diethyl ether and water was acidified with 2N HCl and solid was collected by filtration. Solid was dried under high vacuum to afford 6-((2R,4S)-4-fluoro-2-(5-fluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (1.0 g, yield: 82%). MS (ESI): 430 (M+H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:14][C:15](=[O:46])[C@H:16]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[NH:17][C:18](=[O:38])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[C:35]3[C:34](=[O:36])[N:33]=[C:32]([NH2:37])[NH:31][C:30]=3[NH:29][CH:28]=2)=[CH:21][CH:20]=1)C.O.Cl>[OH-].[Na+]>[NH2:37][C:32]1[NH:31][C:30]2[NH:29][CH:28]=[C:27]([CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][C:19]([C:18]([NH:17][C@H:16]([C:15]([OH:46])=[O:14])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:38])=[CH:24][CH:23]=3)[C:35]=2[C:34](=[O:36])[N:33]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Temperature: 70 °C

Procedure:
N-(4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl)-L-glutamic acid diethyl ester p-toluenesulfonic acid salt (1.0 g) is dissolved in 6.7 mL aqueous sodium hydroxide and stirred until complete solution is obtained. 6 mL of water is added and the pH is adjusted to 3.0-3.5 by the addition of diluted hydrochloride acid. The resulting slurry is heated at 70° C. for an hour and then filtered to yield the title compound in 99.6% purity (HPLC).