Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:31][C@H:32]([C:41]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:42])[CH2:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].C([O-])(O)=O.[Na+].N(C(OCC1C=CC=CC=1)=O)CC(ON1C(=O)CCC1=O)=O>C1COCC1.O.C(Cl)Cl>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:31][C@H:32]([C:41]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:42])[CH2:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:5]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 11 h
Yield: 92.8 %

Procedure:
A mixture of Cbz-Gly-OH (6280 mg, 30 mmol), SuOH (3450 mg, 30 mmol) and DCC (6190 mg, 30 mmol) in dry THF (50 mL) was place d in refrigerator at 5° C. for 11 hours. The precipitated urea was filtered off and the filtrate was evaporated. The evaporated residue was triturated from CHCl3/hexanes and the N-hydroxysuccinimide ester was dried in vacuo (8140 mg, 89%). To a solution of H-Asp(OBut)-Gly-OH (2020 mg, 8.2 mmol) and NaHCO3 (1380 mg, 16.4 mmol) in water (40 mL) was added a solution of Cbz-Gly-OSu (2520 mg, 8.2 mmol) in THF (40 mL) and the mixture was stirred at r.t. for two hours. The mixture was added CH2Cl2 (200 mL) and washed with 1N HCl (200 mL) and water (200 mL). The organic layer was evaporated to give the titled compound (3330 mg, 93%): 1H NMR (300 MHz, DMSO-d6) δ 12.552 (s, 1H), 8.169 (m, 2H), 7.450 (t, J=6.0 Hz, 1H), 7.386 (s, 5H), 5.018 (s, 2H), 4.650 (qd, J=7.3, 2.4 Hz, 1H), 3.8-3.5 (m, 4H), 2.641 (dd, J=15.9, 5.4 Hz, 1H), 2.424 (dd, J=15.9, 8.1 Hz, 1H), 1.363 (s, 9H); 13C NMR (300 MHz, DMSO-d6) δ 171.0, 170.7, 169.2, 169.0, 156.5, 137.0, 128.4, 127.8 (2C), 80.2, 65.5, 49.2, 43.5, 40.8, 37.7, 27.7.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cccc(C(=O)O)c1
Product: CC(C)(C)C1=CC(=Nc2cccc(C(=O)O)c2)C=C(C(C)(C)C)C1=O

Procedure:
Using the method of Example 1, 2,6-di(tertiary-butyl)-p-benzoquinone was reacted with 3-aminobenzoic acid to provide red-orange crystals of 2,6-di(tertiary-butyl)-4-(3'-carboxyphenylimino)-2,5-cyclohexadien-1-one, m.p. 230°-231° C. Analysis: Calculated for C21H25NO3 : % C, 74.3; % H, 7.4; % N, 4.1; Found: % C, 74.1; % H, 7.6; % N, 3.7.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:8].[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2)#[N:14]>C(Cl)(Cl)Cl>[Cl:8][C:15]1([C:13]#[N:14])[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2
Reactant: N#CC1CC2C=CC1CC2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#CC1(Cl)CC2C=CC1CC2
Yield: 94.8 %

Procedure:
To a refluxing mixture of pyridine (14.2 g, 0.180 mol), phosphorus pentachloride (28.0 g, 0.135 mol), and chloroform (100 mL) was added drop-wise a solution of 5-cyanobicyclo[2,2,2]oct-2-ene (12 g, 90 mmol) in chloroform (50 mL). The resulting mixture was heated at reflux for 15 h, cooled, and poured onto ice. The organic layer was concentrated, and the residue was purified by chromatography on silica gel, eluting with mixtures of ethyl acetate (0.5% to 1%) in petroleum ether, to give 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (14.3 g, 95% yield) as a white semisolid, 1H NMR (300 MHz, CDCl3) δ 1.3-1.5 (m, 3H), 2.02-2.18 (m, 2H), 2.51 (m, 1H), 2.72 (m, 1H), 3.12 (m, 1H), 6.22 (m, 1H), 6.41 (m, 1H); GCMS (m/z); 167.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22](=[O:24])[CH3:23])[CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].O>O1CCCC1>[OH:24][CH:22]([CH3:23])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(CC(C(C)=O)c2ccc([N+](=O)[O-])cc2)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Temperature: -78 °C
Yield: 66.4 %

Procedure:
5.48 g of ethyl 5-{2-(4-nitrophenyl)-3-oxobutyl}-2-furancarboxylate in 50 ml of tetrahydrofuran was mixed with 16.5 ml of 1M lithium tri-sec-butylborohydride in tetrahydrofuran under cooling at -78° C. under stirring and stirred at the same temperature for 2 hours. After addition of water, the reaction solution was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→1/1] to give 3.66 g of the title compound as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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.C(O)C>[C:11]1([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(F)c(Br)cc1F
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(-c2ccccc2)cc1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 107.2 %

Procedure:
4-bromo-2,5-difluoroaniline (10 mmol), benzeneboronic acid (12 mmol), tetrakis(triphenylphosphine)palladium(0) (1 mmol) and potassium carbonate (12 g) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL), H2O (10 mL) and ethanol (5 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 4-phenyl-2,5-difluoroaniline (2.2 g) is yielded.
Reaction SMILES: [C:1]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([CH2:29][CH2:30][SH:31])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2].C[O-].[Na+].[CH2:35]1[O:37][CH:36]1[CH2:38][OH:39].Cl>O.CO>[C:1]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([CH2:29][CH2:30][S:31][CH2:35][CH:36]([CH2:38][OH:39])[OH:37])([F:27])[F:28])([F:24])[F:25])([F:21])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2]
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: OCC1CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC(O)CSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 ml reaction flask is charged with 50 g (0.094 mole) of (CF3)2CF(CF2)6C2H4SH, 5.1 g (0.094 mole) of sodium methoxide and 100 ml of methanol. To this is slowly added glycidol while maintaining the temperature at 25°C with an ice bath. After addition is completed, the reaction mixture is stirred for 3 hours, and then there is added 150 ml of water and enough concentrated hydrochloric acid to neutralize the base. Extraction with 1,1,2-trichloro-1,2,2-trifluoroethane and evaporation of solvent affords 53 g of (CF3)2CF(CF2)6C2H4SCH2CH(OH)CH2OH, m.p. 92°-95°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[C:7]=2[N:8]=1.[C:16](=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C.O>ClCCl>[CH3:16][O:13][C:9]1[C:7]2[N:8]=[C:3]([C:2]([F:1])([F:14])[F:15])[N:4]=[CH:5][C:6]=2[CH2:12][CH2:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NCCc2cnc(C(F)(F)F)nc21
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC1=NCCc2cnc(C(F)(F)F)nc21
Reaction time: 5.5 h

Procedure:
To a vigorously stirred mixture of 336 mg (1.33 mmol) of 2-(trifluoromethyl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one and 2.94 g (27.7 mmol) of anhydrous sodium carbonate in 15 mL of dichloromethane was added 979 mg (6.6 mmol) of trimethyloxonium tetrafluoroborate. Vigorous stirring was continued at room temperature for 5.5 h. Then 15 mL of water was added, and the mixture was shaken. After separation of the phases, the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0-2% methanol in dichloromethane) yielded the title compound as a yellow solid. LC-MS 232 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=O)[CH2:4][CH3:5].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:4]([C@@H:3]1[CH2:2][O:1][C:7]([C:9]2[NH:10][C:11]([C:14]3[CH:19]=[C:18]([CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=3)[O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[N:23][CH:22]=3)=[CH:12][CH:13]=2)=[N:6]1)[CH3:5]
Reactant: CC[C@H](CO)NC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O[C@@H](C)COC)c2)[nH]1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
N-[(1R)-1-(Hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.18 g, 2.28 mmol) synthesized in Example (85a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.82 g, 4.56 mmol) and triethylamine (1.27 mL, 9.12 mmol) were added, followed by stirring at 50° C. for 1.5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-70%) to afford the desired compound (1.06 g, yield 93%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][CH:23]=[N:24][CH:25]=2)[N:20]=1>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][CH:23]=[N:24][CH:25]=2)[N:20]=1
Reactant: CCCCN
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncncc2[nH]1
Agent: Cl
Product: CCCCNS(=O)(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
Prepared analogously to Example 51 from n-butylamine and 8-(2'-methoxy-4'-chlorosulfonyl-phenyl)-purine hydrochloride. After the reaction finished, the aqueous phase wsa extracted with ethyl acetate. The residue remaining after the ethyl acetate phases were evaporated was digested with ethanol, subjected to suction filtration, and washed with water.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH2:27][CH2:28][CH3:29])([O-:26])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:27]([N+:24]([O-:26])=[O:25])[CH2:28][CH3:29])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCC(=Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Temperature: 160 °C
Yield: 44.9 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (24.23 g, 100 mmol) and ammonium acetate (7.73 g, 100 mmol) were covered with 1-nitropropane (90 mL, 1008 mmol) and heated to 160° C. for 22 h. The reaction mixture was then cooled to room temperature and the excess of 1-nitropropane was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with water (100 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was boiled up in ethanol (100 mL). After cooling to room temperature the yellow precipitate was collected on a sinter funnel and washed with ethanol (4×30 mL). The solid was dried in vacuo to give the title compound as yellow powder (14.07 g, 44%). 1H NMR (270 MHz, CDCl3) δ 1.14 (3H, t, J 7.3, CH2CH3), 2.71 (2H, q, J 7.4, CH2CH3), 3.93 (3H, s, OCH3), 5.19 (2H, s, OCH2Ph), 6.91 (1H, d, J 1.9, CH), 6.94 (1H, d, J 8.5, CH), 7.05 (1H, dd, J 8.4, CH), 7.25-7.48 (5H, m, OCH2C6H5), 7.91 (1H, s, HC═CNO2).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1N(C2C=CC=CC=2)C2C(C=1)=CC=CC=2)(C)(C)C.[CH3:39][Si:40]([C:43]#[CH:44])([CH3:42])[CH3:41]>[Cu]I.CN(C)CCN(C)C>[CH3:39][Si:40]([C:43]#[C:44][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1)([CH3:42])[CH3:41]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C1CC1c1ccc(I)cc1
Agent: [Cu]I
Agent: CC(C)(C)P(c1cc2ccccc2n1-c1ccccc1)C(C)(C)C
Agent: CN(C)CCN(C)C
Product: COC(=O)C1CC1c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared from and according to the general procedure A dry Schlenk flask was charged with methyl 2-(4-iodophenyl)cyclopropanecarboxylate (1.66 g, 5.49 mmol), Na2[PdCl4] (18 mg, 0.06 mmol), 2-(di-tert-butylphosphino)-1-phenylindole (37 mg, 0.11 mmol), CuI (21 mg, 0.11 mmol), and tetramethylethylenediamine (10 mL). The mixture was evacuated and backfilled with Ar (3×), and heated to 70° C. before addition of trimethylsilylacetylene (1.4 mL, 10.8 mmol) through the septum and the temperature was elevated to 80° C. After consumption of the starting material indicated by HPLC, the reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum and a fraction of the residue was purified by flash chromatography to give 580 mg (40%) after purification by flash chromatography (SiO2, EtOAc:PE, 1:8): Rt: 14.56 min (HPLC method I).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(N)c2)c1
Yield: 41.7 %

Procedure:
The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (400 mg, 1.2 mmol), 3-aminophenylboronic acid (361 mg, 2.3 mmol, Aldrich Chem. Co.), Pd(0) (35 mg) and Na2CO3 (1.5 mL of a 2 M solution) were mixed in 8 mL of toluene, and the mixture was stirred at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with exane:Et2O 1:1, to afford 178 mg of the title compound. MS (CI/NH3) m/z 356 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H), 3.92 (m, 2H), 4.20 (m, 1H), 4.38 (m, 1H), 4.55 (m, 1H), 6.72 (m, 1H), 6.88 (s, 1H), 6.97 (m, 1H), 7.44 (m, 2H), 8.31 (m, 1H), 8.44 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]1=[O:19])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]=1[O:19][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH3:2]
Reactant: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1=C(OC(=O)C(C)(C)C)C(C)(C)OC(C)C1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
To a solution of 4-(3-ethyl-4′-fluoro-biphenyl-4-yl)-2,2,6-trimethylpyran-3,5-dione (0.125 g, 0.35 mmol) in dichloromethane (5 ml) is added triethylamine (0.2 ml, 1.43 mmol) and the reaction mixture is cooled to 0° C. Pivaloyl chloride (0.2 ml, 1.63 mmol) is added slowly at 0° C. and the mixture is stirred at 0° C. for 5 hours. The reaction mixture is diluted with water and extracted with dichloromethane (3×25 ml). The organic extracts are combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to afford 2,2-dimethyl propionic acid 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethyl-5-oxo-5,6-dihydro-2H pyran-3-yl ester (130 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:12].[H][H]>CO.[Pd]>[NH2:8][C:7]1[CH:6]=[C:5]([OH:11])[CH:4]=[C:3]([CH3:12])[C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(N)c1N

Procedure:
2.00 g (11.06 mmol) 4-amino-3-methyl-5-nitrophenol were placed in 50 mL methanol and hydrogenated under a hydrogen atmosphere and with the addition of 1.00 g Pd/C (10%) at 50° C. and a hydrogen pressure of 5 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:26]([NH2:28])[CH3:27]>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:28][CH2:26][CH3:27])=[O:4]
Reactant: CCN
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 37 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 5.0 g of anhydrous sodium sulfate were added. The mixture was heated at 60° C. for 6 hours. Subsequently, sodium sulfate was filtrated off. To the filtrate, 20 g (310 mmol) of 70% ethylamine was added and the same procedure as in Example 1 was performed to obtain 2.0 g of theanine (yield: 37.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=3[F:21])[N:11]=[N:10][N:9]=2)=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][CH2:31][CH2:32]Br.[I-].[Na+]>[Cl-].[Na+].O.O.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:22])[CH:6]=3)=[N:9][N:10]=[N:11]2)=[C:14]([F:21])[C:15]=1[F:20]
Reactant: Nc1ncc(Br)cc1-c1nnnn1-c1ccc(O)c(F)c1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1ccc(-n2nnnc2-c2cc(Br)cnc2N)c(F)c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a stirred suspension of Compound 1086 (300 mg, 0.8127 mmol), potassium carbonate (224.6 mg, 1.625 mmol), and 2-bromoethyl methyl ether (169.4 mg, 114.5 μL, 1.219 mmol) was added sodium iodide (182.7 mg, 1.219 mmol). The reaction mixture was heated to 50° C. and allowed to stir overnight. After cooling, the mixture was partioned between EtOAc and water. The organics were with brine, dried over sodium sulfate, and the volatiles removed in vacuo. Purification by silica gel chromatography (0-50% gradient of EtOAc/hexanes) gave 3-(1-(4-(2-methoxyethoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (Compound 1089, 120 mg).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH:20]=[O:21])[C:16]#[CH:17]>C1C=CC=CC=1>[CH2:15]([N:18]([CH:19]([CH2:22][O:23][CH3:24])[CH:20]=[O:21])[C:13]([NH:12][C:10]1[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][N:9]=1)=[O:14])[C:16]#[CH:17]
Reactant: C#CCNC(C=O)COC
Reactant: CCCCCCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C#CCN(C(=O)Nc1nnc(CCCCCC)s1)C(C=O)COC

Procedure:
5-Hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propargylamino-3-methoxy-propionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-hexyl-1,3,4thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([OH:28])=O)=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[C:33]([C:39]([NH:41][CH3:42])=[O:40])[CH:32]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:26]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][C:33]=2[C:39]([NH:41][CH3:42])=[O:40])=[O:28])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1ccccc1

Procedure:
The title compound was prepared from 3-benzyloxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid using a procedure similar to that described in Example 2, Step 5, except that 4-fluoro-2-[(methylamino)carbonyl]benzylamine hydrochloride was used in place of 4-fluorobenzylamine. 1H NMR (400 MHz, d6-DMSO) δ 8.51 (d, J=4.8 Hz, 1H), 8.38 (t, J=4.0 Hz, 1H), 7.43-7.24 (m, 11H), 6.92-6.91 (m, 2H), 5.78-5.77 (m, 1H), 5.36 (dd, J=10.8, 38.4 Hz, 2H), 4.46 (dd, J=6.0, 18.4 Hz, 2H), 4.23 (dd, J=4.4, 13.6 Hz, 1H), 3.81 (dd, J=3.2, 13.6 Hz, 1H), 2.89 (s, 3H), 2.73 (s, 3H); ES MS (M+1)=542.