Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:24][C:25]([NH2:27])=[O:26])=[C:9]([CH2:22][CH3:23])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].O.C(OCC)(=O)C>CO>[NH2:27][C:25](=[O:26])[CH2:24][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:28])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[CH2:22][CH3:23]
Reactant: CCc1c(CC(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCc1c(CC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester and 2 mL of 1M NaOH in 6 mL of MeOH Tunas heated to dissolve all materials and then stirred at room temperature for 1 hour. Water and ethyl acetate were added and the aqueous layer separated, made acidic to pH 3 with 1N HCl and ethyl acetate added. The insoluble material was filtered. The ethyl acetate solution gas washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was combined with the filtered material above to give 90 mg (95% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, mp, 220-222° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH2:34]([O:33][C:31]([CH2:30][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28])=[O:32])[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 100 °C
Reaction time: 21 h
Yield: 66 %

Procedure:
1.02 g (2.62mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 30 mL of dimethylformamide under argon atmosphere, 5.8 mL (52.3 mmol) of ethyl bromoacetate and 1.80 g (13.1 mmol) of potassium carbonate were added and the mixture was stirred at 100° C. for 21 hours. The reaction solution was cooled on ice, an aqueous saturated solution of ammonium chloride was added and the precipitated crystals were collected by filtration. The mother liquor was extracted with ethyl acetate, and the organic layer was washed with water and with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was added to the above crystals and the mixture was purified by silica gel column chromatography (chloroform:acetonitrile=25:1) to give 824 mg of 5-ethoxycarbonylmethylamino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 66%).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[C@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.Br[C:41]1[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([NH:8][C@H:9]1[C@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:41]2[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NCc3ccccc3)C2)nc1C
Yield: 20.9 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-3-(benzylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (203a) (50.0 mg, 0.108 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (32 mg, 0.130 mmol) and sodium carbonate (115 mg, 1.08 mmol), to obtain 12 mg of the title compound (21%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([CH:27]1[CH2:29][CH2:28]1)[CH2:20]2)[CH2:5][N:6]1[CH2:10][C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13].[CH3:30]B1OB(C)OB(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:27]1([N:21]2[CH2:20][C:19]3[C:23](=[CH:24][CH:25]=[C:17]([C:16]4[CH:15]=[CH:14][C:4]([CH2:5][N:6]5[CH2:10][C:9](=[O:11])[N:8]([CH3:12])[C:7]5=[O:13])=[CH:3][C:2]=4[CH3:30])[CH:18]=3)[C:22]2=[O:26])[CH2:28][CH2:29]1
Reactant: CB1OB(C)OB(C)O1
Reactant: CN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)c(Cl)c2)C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(CN2CC(=O)N(C)C2=O)ccc1-c1ccc2c(c1)CN(C1CC1)C2=O
Yield: 39.4 %

Procedure:
1-(3-chloro-4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dione (0.073 mmol, 30 mg), trimethylboroxine (0.110 mmol, 27.6 mg), tris(dibenzylideneacetone)dipalladium(0) (3.66 μmol, 3.4 mg), tricyclohexylphosphine (8.78 μmol, 2.5 mg) and potassium phosphate, tribasic (0.124 mmol, 26.4 mg) were suspended in dioxane (750 μL) and water (250 μL) and heated under microwave irradiation at 130° C. for 30 minutes. The solvent was removed under reduced pressure and the mixture partitioned between water and dichloromethane. The organic layer was separated using a hydrophobic frit and concentrated. Purified by acidic prep HPLC to afford 1-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)-3-methylbenzyl)-3-methylimidazolidine-2,4-dione (11.2 mg, 39%); 1H NMR (400 MHz, CDCl3) 7.86 (d, 1H), 7.36 (dd, 1H), 7.31 (d, 1H), 7.21-7.12 (m, 3H), 4.58 (s, 2H), 4.36 (s, 2H), 3.79 (s, 2H), 3.07 (s, 3H), 2.96 (m, 1H), 2.24 (s, 3H), 0.97-0.87 (m, 4H). LCMS (M+H) 390.2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.B1(C2C=CC(N)=CC=2)OC(C)(C)C(C)(C)O1>>[CH:15]([N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:5]2[N:6]=[N:7][C:2]([C:22]3[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCCN(c2ccc(Cl)nn2)CC1
Reactant: Nc1ccc(B(O)O)cc1
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC(C)N1CCCN(c2ccc(-c3ccc(N)cc3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1-(6-chloro-pyridazin-3-yl)-4-isopropyl-perhydro-1,4-diazepine and 4-aminophenylboronic acid, pinacol cyclic ester. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.53 (d, 1H), 6.76 (m, 3H), 3.86 (t, 2H), 3.77 (m, 4H), 2.93 (heptet, 1H), 2.81 (m, 2H), 2.58 (m, 2H), 1.95 (m, 2H), 1.00 (d, 6H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCCC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCCC1
Yield: 98.2 %

Procedure:
A solution of 1-cyclohexyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (60 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (67 mg), tetrakis(triphenylphosphine)palladium(0) (18 mg) and 2M aqueous sodium carbonate solution (0.40 mL) in DME (10 mL) was stirred under nitrogen atmosphere at 100° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (60 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:16]([OH:20])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[C:4]([NH:6][C:7](=[S:8])[O:20][CH2:16][CH2:17][CH2:18][CH3:19])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCCCO
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=S)NC(=O)OCC
Yield: 95.8 %

Procedure:
26 g of ethoxycarbonyl isothiocyanate were added dropwise to a mixture of 0.4 ml of triethylamine, 15 g of normal butanol and 150 ml of tetrahydrofuran and the mixture was refluxed for 2 hours and concentrated to dryness by distillation under reduced pressure to obtain 39 g of raw n-butyl N-carbethoxy-thiocarbamate. The latter product was added to a mixture of 500 ml of methanol and 14 g of potassium methylate and the mixture was stirred for an hour and then concentrated to dryness under reduced pressure. The residue was added to ether and the precipitate formed was recovered by vacuum filtration and was dried to obtain 35 g of the potassium salt of n-butyl N-carbethoxy-thiocarbamate melting at 219° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[OH-].[Na+]>O>[CH2:20]([O:19][C:17]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
Nipecotic acid (3.93 g, 30.4 mmol) and sodium carbonate (5.10 g, 48.1 mmol) in water (40 mL) was mixed with benzyl chloroformate (5.20 mL, 36.4 mmol) under cooling with ice and stirred at room temperature for one day. After addition of water and 1 M aqueous sodium hydroxide, the reaction mixture was allowed to separate by adding diethyl ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a pale yellow oil (5.86 g, yield 73%).
Reaction SMILES: [N:1]1([C:7]#[N:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:9][O-:10].[Na+]>CO>[N:1]1([C:7](=[NH:8])[O:10][CH3:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: N#CN1CCOCC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCOCC1

Procedure:
In the manner given in Example 2, 4-morpholinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-morpholinecarboximidate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cccc(F)c1)(c1cccc(F)c1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC(c1cccc(F)c1)(c1cccc(F)c1)C1CCNCC1
Yield: 92 %

Procedure:
A solution of 39.3 g (0.1 mol) of the base of α,α-bis(3-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol in 750 ml of absolute ethanol was hydrogenated over 1 tsp of 5% Pd/C in a Parr apparatus at 50 psi and 60° C. for 3.5 days. The mixture was cooled and filtered through Celite®. The filtrate was concentrated, and the residue was dissolved in ethyl ether and filtered through cotton to remove some insoluble material. The filtrate was concentrated to give a gum which crystallized when triturated with petroleum ether (30°-60° C.). The solid was collected by filtration and dried to yield 27.9 g (92%) of white solid. An analytical sample, mp 117°-118° C., was recrystallized from isopropyl ether/2-propanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:14](/[N:21]=[C:8](\[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)/[C:9]([F:12])([F:11])[F:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(Br)cn1)C(F)(F)F
Reactant: NCc1ccccc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: FC(F)(F)/C(=N/Cc1ccccc1)c1ccc(Br)cn1
Reaction time: 3 h
Yield: 4.4 %

Procedure:
To a solution of 1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethanone (7.5 g, 29.52 mmol) in dry toluene (30 mL) is added bezylamine (3.15 g, 29.52 mmol) and titanium ethoxide (7.4 g, 32.48 mmol) at room temperature then stir for 3 hours. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 20% ethyl acetate in hexane to afford the title compound (0.45 g). LC-MS (m/z): [M+H]=345.0.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([P:34](=[O:37])([OH:36])[OH:35])[CH3:33])=[O:30])[CH2:26][CH2:27][CH3:28])=[O:23])[CH3:21])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([P:34](=[O:35])([OH:37])[OH:36])[CH3:33])=[O:30])[CH2:26][CH2:27][CH3:28])=[O:23])[CH3:21]
Reactant: CCC[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-alanyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-alanyl-L-norvalylamino)-ethylphosphonic acid of melting point 268°-270° C.; [α]D20 =-50.4°; [α]36520 =-201° (c=0.46%, a freshly prepared solution in 1-N sodium hydroxide).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])[CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: Fc1cccc(CBr)c1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc2cc(N(Cc3cccc(F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Fluorobenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].C(OC)(C)(C)C>C(OC(=O)C)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[CH:10]2)[CH2:8]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
The cis/trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester mixture is prepared as described in Example 47(a) of WO 97/28161. The cis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester is isolated from the cis/trans mixture by chromatography on silicagel (t-butyl-methyl-ether:ethylacetate=1:1). Analytical HPLC: tR=10.59 min (Grad 1); ES-MS m/eo=429.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:6]=1[C:21]1[N:22]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:23]([SH:26])=[N:24][N:25]=1.Cl>CO>[SH:26][C:23]1[N:22]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:21]([C:6]2[CH:7]=[C:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]([OH:11])=[CH:10][C:5]=2[OH:4])=[N:25][N:24]=1
Reactant: COCOc1cc(OCOC)c(-c2nnc(S)n2-c2cccc3ccccc23)cc1-c1ccccc1
Agent: Cl
Solvent: CO
Product: Oc1cc(O)c(-c2nnc(S)n2-c2cccc3ccccc23)cc1-c1ccccc1
Temperature: 50 °C
Yield: 76.7 %

Procedure:
To the intermediate (400 mg, 0.77 mmol) was added degassed 2N—NaOH (0.7 mL, 0.35 mmol) and the reaction mixture was stirred at 110° C. for 2 h. After cooled down to room temperature, the reaction mixture was acidified with 1N—HCl. The white precipitate was filtered and dried to give 5-(4,6-Bis-methoxymethoxy-biphenyl-3-yl)-4-naphthalen-1-yl-4H-[1,2,4]triazole-3-thiol as a white solid (250 mg, 65%). 5-(4,6-Bis-methoxymethoxy-biphenyl-3-yl)-4-naphthalen-1-yl-4H-[1,2,4]triazole-3-thiol (190 mg, 0.38 mmol) was dissolved in MeOH (7 mL) and 6N—HCl (0.5 mL) was added to the solution. The reaction mixture was heated at 50° C. for 2 h. After MeOH was removed under vacuum, the reaction mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine and dried over MgSO4. The purification of the concentrated crude product by column chromatography (MeOH 10% in CH2Cl2) afforded the title product as white solid (120 mg, 77%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[F:16][C:17]1[C:22]([F:23])=[C:21]([OH:24])[CH:20]=[CH:19][C:18]=1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:36]=2)=[CH:27][N:26]=1.[C:46](O)(=[O:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>CN(C1C=CN=CC=1)C.ClCCl>[C:46]([O:24][C:21]1[CH:20]=[CH:19][C:18]([C:25]2[N:30]=[CH:29][C:28]([C:31]3[CH:32]=[N:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:35][CH:36]=3)=[CH:27][N:26]=2)=[C:17]([F:16])[C:22]=1[F:23])(=[O:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OC(=O)CCCCCC)c(F)c3F)nc2)cn1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
2.7 mmol of DCC are introduced at room temperature into 50 ml of dichloromethane, and 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine, 2.7 mmol of heptanoic acid and 0.24 mmol of DMAP are added. The reaction mixture is left to stand overnight with exclusion of light, precipitated dicyclohexylurea is then filtered off, and the solvent is removed in vacuo. The crude product is chromatographed on silica gel 60 using dichloromethane/ethyl acetate 20:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 1.0 g (84%) of colorless crystals, X 88 SC 165 SA 167.5 I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]([O:30]CC)=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]([OH:30])=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)c(Cl)c1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1Cl)c1ccc(-c2ccccn2)cc1
Yield: 78.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[3-chloro-4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-phenoxypropionate (540 mg), which is the product of Example 161, was reacted with aqueous sodium hydroxide solution (1N, 1.98 ml) and the reaction mixture was treated to give the title compound (404 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:14]=3[C:15]([NH:17][C:18]3([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:20][CH2:19]3)=[O:16])[CH2:10]2)=[N:6][CH:7]=1.[OH-].[Na+]>C1OCCOC1.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[N:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:14]=3[C:15]([NH:17][C:18]3([C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=4)[CH2:19][CH2:20]3)=[O:16])[CH2:10]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ncc(F)cn4)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ncc(F)cn4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
To a solution of methyl 4-(1-(2-(3-((5-fluoropyrimidin-2-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)cyclopropyl)benzoate (D182) (35 mg, 0.065 mmol) in a mixture 1-4 dioxane/water (3 ml/1 ml) 1M NaOH (0.098 ml, 0.098 mmol) was added. The mixture stirred 24 h at room temperature. After solvent evaporation, 1N HCl solution was added up to pH2. The solid precipitate was filtered off and washed with diethylether to afford the title compound (E48) (27 mg)