Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:31])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd].C>[CH3:30][O:29][C:26]1[N:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[NH:18][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:31]
Reactant: COc1ccc2nccc(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2nccc(NC(=O)C3CCNCC3)c2n1
Yield: 58.6 %

Procedure:
A solution of (e) (6.0 g, 14.3 mmol) in ethanol/ethyl acetate (150 ml/150 ml) was hydrogenated over 10% Pd/charcoal (5 g) for 1.5 hours. Filtration, washing with ethanol (400 ml) and evaporation of the filtrate gave a white solid (2.4 g, 59%).
Reaction SMILES: C([Li])CCC.C(#N)C.[CH2:9]([O:16][C:17]1C=C(OC(CCCC2C=CC=CC=2)C)C=[C:21]2[C:26]=1[CH:25](C(OC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:24][C:23](C)(C)[CH2:22]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:26]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(CCCc1ccccc1)Oc1cc2c(c(OCc3ccccc3)c1)C(C(=O)Oc1ccc([N+](=O)[O-])cc1)CC(C)(C)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.4 ml. of 2.1M n-butyllithium in 3.7 ml. tetrahydrofuran at -78° C. is added a solution of 0.26 ml. (5 mmole) acetonitrile in 3.7 ml. THF and the mixture is stirred for one hour. at -78° C. A solution of 1.1 g. (2.0 mmole) p-nitrophenyl 8-benzyloxy-3,3-dimethyl-6 -(5-phenyl-2-pentyloxy)tetralin-1-carboxylate in 3.7 ml. THF is added and stirring continued at -78° C. for 30 minutes. The reaction mixture is warmed to room temperature, quenched with 7 ml. 10% hydrochloric acid and extracted with ethyl ether. Isolation of product as in the preceding Example affords 1.13 g. of crude benzyl ether which gives 500 mg. of purified intermediate by silica gel chromatography: mass spectrum-molecular ion, 495.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Cl-].[Na+].O.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:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:15]=[C:14]3[C:5]([CH2:6][C:7]4([C:13]53[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]5)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1=NC2(N=C1N)c1cc(-c3cccc(Cl)c3)ccc1CC21CCOCC1
Temperature: 130 °C
Yield: 43.1 %

Procedure:
A mixture of 6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine (Example 25, 75 mg, 0.22 mmol), 3-chlorophenylboronic acid (40.4 mg, 0.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (8.86 mg, 10.77 μmol), 2 M aq. K2CO3 (0.215 mL, 0.43 mmol) and 1,4-dioxane (2 mL) were mixed in a vial and heated in a microwave reactor at 130° C. for 15 min. When cooled to r.t., the mixture was diluted with brine (3 mL) and extracted with DCM (3×3 mL). The combined organics were concentrated and the resulting residue was purified by preparative chromatography. The fractions containing the title compound were pooled, the solvent removed in vacuo, and the resulting aqueous residue was extracted with DCM (3×3 mL). The combined organics were passed through a phase separator and concentrated. The resulting residue was taken up in MeOH (2 mL) and dried in a vacuum oven at 40° C. over a weekend to give 36 mg (44% yield) of the title compound; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.55 (t, 1H), 7.49 (m, 2H), 7.39 (m, 3H), 6.80 (d, 1H), 6.61 (br. s, 1H), 3.66 (m, 2H), 3.48 (m, 1H), 3.40 (td, 1H), 3.22 (d, 1H), 3.08 (d, 1H), 2.19 (s, m 3H), 1.72 (td, 1H), 1.22 (m, 3H); MS (ES+) m/z 380 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:32])[N:12]([CH:29]([CH3:31])[CH3:30])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH:29]([N:12]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])[C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([O:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:3]2)[S:7][CH:8]=1)=[O:32])([CH3:30])[CH3:31]
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Yield: 45.8 %

Procedure:
A solution of 3-hydroxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (1.43 g, 3.09 mmol) (obtained as described in Reference Example 60(3)) in methylene chloride (72 ml) were added methanesulfonyl chloride (0.29 ml, 3.70 mmol) and triethylamine (0.52 ml, 3.70 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (20:1) as the eluant to afford 1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (766 mg, yield 46%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:19]2[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=2[O:21][CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(OC)cc1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Solvent: O
Product: COc1ccc(OC)c(C(=O)Cc2ccc(F)c(F)c2)c1
Temperature: 50 °C
Yield: 25.6 %

Procedure:
3,4-Difluorophenylacetic acid (3.0 g, 17.4 mmol) and 1,4-dimethoxybenzene (3.6 g, 26.1 mmol) in polyphosphoric acid (50 g) was heated at 72° C. for 3 h. The reaction was cooled to 50° C., and H2O (70 mL) was added. The resulting mixture was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified on a silica gel column to give 2-(3,4-difluorophenyl)-1-(2,5-dimethoxyphenyl)ethanone (1.3 g) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.40-7.25 (m, 2H), 7.14-7.10 (m, 3H), 7.08-7.7.03 (m, 1H), 4.29 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C@H:15]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:17])(OC(C)(C)C)=O.[CH2:44]=O>>[CH3:44][CH:13]([NH:14][C@H:15]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:17])[C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: C=O
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(C)[C@H]2CCCN2)C1

Procedure:
The title compound was prepared following the procedure described in Example 3 using (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 3 and formaline.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:12][C:11]1([CH3:19])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 1-octyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, methacryloyl chloride and triethylamine in methylene chloride to afford the title compound as a colorless oil. Analyses by nmr, ir and ms give data consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4ccccc4c3)cc2)ccc1Cl
Yield: 34.1 %

Procedure:
2-(4-Aminophenylthio)naphthalene (4.2 mmoles, 1.06 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (4.2 mmoles, 0.93 g) were reacted according to procedure A to yield of the title compound 0.7 g, 34%. Mass Spec (FD) 489. Calculated for C24H16ClF3N2S2 : C,; H, N, Found: C,; H,; N,.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8]>>[C:17]([C:13]1[CH:14]=[C:15]([CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]=1[OH:21])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 140 °C

Procedure:
The reaction was heated to 140° C. to remove the water/toluene azeotrope. A white slurry was obtained and 7.2 g hazy toluene was collected in the trap. The Dean-Stark trap was removed and a cooling condenser was connected to the reactor. The heating was reset to 120° C. Vigorous condensation was observed and 99.1 g (1.15 mol) of methyl acrylate was added over a 45-minute period. After three hours of heating at 120° C., the 2,6-di-tert-butylphenol conversion was about 98.5% complete.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: COc1ccc2c(-c3ccc(F)c(F)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:12]#[C:13][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=3)[N:7]=2)=[CH:15][CH:16]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (780 mg, 3.0 mmol, 1 eq) and 4-ethynylaniline (543 mg, 1.5 eq) in anhydrous DMF (10 mL) under nitrogen atmosphere was added triethylamine (1.67 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (210 mg, 0.1 eq) and copper(I) iodide (114 mg, 0.2 eq). After the reaction mixture was stirred at 50° C. for 30 minutes, it was partitioned between saturated aqueous sodium bicarbonate and chloroform (containing 3% v/v of MeOH). The organic layer was separated and washed with aqueous ammonium chloride, brine, and lastly dried with anhydrous sodium sulfate. The upper suspension mixture was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (from CHCl3 to MeOH—CHCl3 1:30) to give 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as a yellow solid in amount of 166 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]([N+:18]([O-])=O)=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:21])=[N:12]3)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(=O)C.Cl.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]([NH2:18])=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:21])=[N:12]3)[CH2:3][CH2:2]1
Reactant: Cc1ccc2c(N3CCOCC3)c(F)cc([N+](=O)[O-])c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(N3CCOCC3)c(F)cc(N)c2n1
Yield: 80.5 %

Procedure:
Stannous chloride dihydrate (5.7 g) was added to a solution of 1.8 g of 5-morpholino-6-fluoro-8-nitroquinaldine in 30 ml of acetic acid and 20 ml of concentrated hydrochloric acid was added dropwise to the mixture with stirring. After completion of addition the mixture was stirred at room temperature for 1 hour, diluted with water and rendered alkaline with an aqueous sodium hydroxide solution to form precipitations, which then were extracted with dichloromethane, after drying over magnesium sulfate the solvent was distilled off to give 1.30 g of 5-morpholino-6-fluoro-8-aminoquinaldine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:7][C@H:8]([C:23](=[O:40])[N:24]([C:26]1[N:30](CC2C=CC(OC)=CC=2)[N:29]=[N:28][N:27]=1)[CH3:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:6])[CH3:2].C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:7][C@H:8]([C:23](=[O:40])[N:24]([CH3:25])[C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:14][CH:15]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)N(C)c1nnnn1Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)N(C)c1nnn[nH]1
Yield: 58.2 %

Procedure:
Next, (S)-2-((S)-2-(3′-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}-ethylamino)-propionic acid ethyl ester (260 mg, 0.451 mmol) was dissolved in TFA (5 mL) and DCM (5 mL) and stirred at 50° C. for 12 hours and at 75° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give (S)-2-{(S)-2-(3′-chloro-biphenyl-4-yl)-1-[methyl-(1H-tetrazol-5-yl)-carbamoyl]-ethylamino}-propionic acid ethyl ester (120 mg). MS: m/z (MW) 457; HPLC retention time 0.95 min (HPLC condition C).
Reaction SMILES: [NH2:1][CH:2]([C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1)[CH3:3].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[C:9]1([C:4]2([CH:2]([NH:1][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: CC(N)C1(c2ccccc2)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(C)C1(c2ccccc2)OCCO1

Procedure:
A solution of 2-(1-aminoethyl)-2-phenyldioxolane (20 mmoles), triethylamine (24 mmoles), and ethyl chloroformate (22 (mmoles) in 100 ml of dichloromethane is stirred at 0°C for 2 hours, washed with water, dried, and evaporated to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=3)[C:12]([CH2:22][CH3:23])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.CN(C=O)C.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.O.N1C=CC=CC=1>[N:33]1[CH:34]=[CH:35][C:30]([NH:29][C:19]([C:16]2[CH:17]=[C:18]3[C:13]([C:12]([CH2:22][CH3:23])=[N:11][N:10]3[CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:21])=[CH:31][CH:32]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Reactant: Nc1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
46 μL (0.629 mmol, 1.3 equiv) thionyl chloride were added to a room temperature solution of 125 mg (0.484 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 5 μL DMF in 5 mL anhydrous toluene. The reaction mixture was heated to reflux for 2 hours, then cooled to room temperature, concentrated to dryness on a rotary evaporator, and dried at high vacuum, room temperature for several hours. The crude acid chloride was dissolve din 5 mL anhydrous pyridine, 50 mg (0.532 mmol, 1.1 equiv) 4-aminopyridine were added, and the mixture heated to 40° C. for 1 hour. The reaction mixture was cooled to room temperature and allowed to stand overnight. 10 mL H2O were added, and the mixture was concentrated to dryness on a rotary evaporator. The residue was taken up in 50 mL H2O and 25 mL CH2Cl2, and the layers separated. The aqueous layer was extracted 1×25 mL CH2Cl2. The organic extracts were combined, washed 1×10 mL each H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 133 mg of a white foam, which was purified on a silica gel column (25% CH3OH/CH2Cl2) to give 122 mg of white needles. Recrystallization from ethyl acetate/hexanes gave 101 mg (62%) of white shiny plates: mp 144-146° C.; Anal. calcd for C20H22N4O: C, 71.83; H, 6.63; N, 16.75. Found: C, 72.00; H, 7.03; N, 16.16.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C1\CCc2ccc(F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
An ice-cold, stirred suspension of (E)-2-(6-fluoro-1-indanylidene)acetic acid (384 mg, 2 mmol) in benzene (10 mL) was treated with oxalyl chloride (761 mg, 6 mmol) and allowed to warm to room temperature during 1.5 h. The resulting yellow solution was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetyl chloride as a pale yellow solid (421 mg, 100%), m.p., 97-99° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19](OCC)([CH3:22])[NH:20][N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(C)NN=C(C2CCN(C(=O)OCc3ccccc3)CC2)O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(5-ethoxy-5-methyl-1,3,4-oxadiazolin-2-yl)piperidine (200 mg) in toluene (5 mL) containing pyridine (0.25 mL) was heated under reflux for 20 hours. The mixture was cooled to room temperature, and the solvent was evaporated. The residue was purified by chromatography, eluting with chloroform:methanol:ammoniumhydroxide (98:2:1), to give the 1,3,4-oxadiazole derivative (0.143 g) as a clear oil; NMR (CDCl3): 7.35 (m, 5), 5.13 (s, 2), 4.16 (broad d, 2, J=12.8), 3.05 (m, 1), 2.50 (s, 3), 2.04 (m, 2), 1.83 (m, 2).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:24])[CH3:23])[C@H:17]1[CH3:25].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][CH2:11][C:12]([NH:52][CH2:51][C:48]2[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=2)=[O:13])[N:5]=[CH:4][C:3]=1[NH:15][C@@H:16]1[CH2:21][C@@H:20]2[CH2:22][C@@H:18]([C:19]2([CH3:23])[CH3:24])[C@H:17]1[CH3:25]
Reactant: NCc1ccncc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCC(=O)O)c(=O)c1Br)C2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCCC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Yield: 65.6 %

Procedure:
4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}butanoic acid (38 mg, 0.091 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg, 0.182 mmol), 1-hydroxybenzotriazole anhydride (12 mg, 0.091 mmol) and triethylamine (25 μL, 0.182 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (25 μL, 0.182 mmol) at room temperature for 24 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=15/1) to give the desired product (30 mg, 58% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH3:12])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1cccc(Nc2ccccc2)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2cccc(CCl)c2)c1C
Reaction time: 18 h

Procedure:
To a solution of 3-chloromethylbenzoyl chloride (2.0 g) in methylene chloride (20 mL) was added 2,3- dimethylphenylaniline (1.28 g) and triethylamine (1.47 mL). The solution was stirred 18 h, concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Upon concentration a precipitated formed which was collected and dried to obtained the product. NMR (300 MHz, DMSO-d6) δ 10.0 (1H, s), 8.02 (1H, s), 7.94 (1H, d, J=7 Hz), 7.63 (1H, d, J=7 Hz), 7.52 (1H, t, J=7 Hz). 7.10 (3H, s), 4.83 (2H, s), 2.27 (3H, s), 2.07 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=O>CCCCCC>[CH3:10][C:6]1([CH3:11])[C:7](=[O:9])[C:3]2[C:2]([CH3:1])=[C:14]([CH3:15])[C:13]([CH3:16])=[CH:12][C:4]=2[O:5]1
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1C
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1C)C(=O)C(C)(C)O2
Yield: 90 %

Procedure:
Using 2-(3,4,5-trimethylphenoxy)-2-methylpropionic acid obtained in Reference Example 40, the title compound was synthesized in the same manner as in Reference Example 41. Yield 90%. Melting point: 77-78° C. (hexane).