Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][CH:3]=1.Cl.[N:11](OCCC(C)C)=[O:12]>C(O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[N:11]=[O:12]
Reactant: CC(C)CCON=O
Reactant: Nc1ccnn1CCO
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1CCO
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.3 %

Procedure:
To a solution of 5-amino-1-(2-hydroxyethyl)pyrazole (6.35 g) in a mixed solvent of ethanol (25 ml) and concentrated hydrochloric acid (0.035 ml) was added dropwise isoamyl nitrite (7.03 g). The mixture was stirred at room temperature for 17 hours. The crystalline residue was collected by filtration and dried in vacuo to give 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole (4.0 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]([CH3:14])=[CH2:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:13])[CH3:14])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1
Reactant: C=C(C)c1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(O)c12
Temperature: 25 °C
Reaction time: 27 h
Yield: 80.4 %

Procedure:
A mixture of 8-chloro-2-isopropenyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.26 g), ethyl acetate (10 mL), methanol (5.0 mL) and palladium hydroxide (0.05 g) was stirred at room temperature for 27 hours under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtrated concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) gave title compound as a yellow oil (0.21 g),
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:19])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[BrH:26]>O>[Br:26][C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:19])[N:3]=1
Reactant: Br
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)nc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2ccc(O)cc2)c(Br)n1
Temperature: 110 °C
Yield: 62 %

Procedure:
2-Chloro-3-(4-methoxybenzenesulfonyl)-6-methylpyridine (4.74 g, 15.92 mmol) was suspended in HBr (84 mL, 48%). The orange reaction mixture was heated at 110° C. for 24 h. The reaction mixture was cooled to rt, diluted with H2O, and was treated with Na2CO3 until neutral. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford a colorless solid (3.22 g, 62% yield) which was used without further purification: mp 99–102° C.; 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H), 6.95 (d, J=9.1 Hz, 2H), 2.63 (s, 3H); LRMS (APCI) m/z 328.0 [(M+H)+, calcd for C12H11NO3BrS, 328.0].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:14][CH2:15][CH3:16].[Na+].O>C(O)C>[CH2:15]([O:14][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:16]
Reactant: CC[O-]
Reactant: CCc1cc(Cl)nn2c(N)nnc12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(CC)c2nnc(N)n2n1
Temperature: 45 °C
Yield: 91.3 %

Procedure:
6-Chloro-8-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.003; 700 mg) was dissolved in ethanol (100 ml) while stirring. Thereafter, the reaction mixture was admixed with sodium ethoxide (724 mg) and stirred at RT for 2 h. Subsequently, the mixture was heated to 45° C. for 3 h. After the solvent had been drawn off, the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 670 mg of the title compound were obtained.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:21][NH2:22]>C(Cl)Cl.O>[CH3:21][NH:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-3-nitrobenzoate (25 g, 0.126 mol) was dissolved in DCM (400 ml) and to this was added Potassium carbonate (34.7 g, 0.25 mol) followed by Methylamine (20.63 ml, 0.5 mol). Reaction was stirred at room temperature under argon. Upon completion reaction was diluted with water and extracted with DCM (3×) then dried over magnesium sulfate. Solvents were removed under reduced pressure to afford methyl 2-(methylamino)-3-nitrobenzoate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:12][C:3]1[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(C)(=O)=O)c1Cl

Procedure:
To a solution of methyl 3-amino-2-chlorobenzoate (517 mg, 2.79 mmol) and pyridine (0.25 mL, 3.06 mmol) in 8 mL CH2Cl2 was added methanesulfonylchloride (0.24 mL, 3.06 mmol). After washing with 1M HCl, methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was isolated as a solid in quantitative yield. 1H NMR (400 MHz, CDCl3), δ 7.77 (dd, 1H, J=8.2, 1.6 Hz), 7.61 (dd, 1H, J=7.9, 1.6 Hz), 7.33 (t, 1H, J=7.9 Hz), 7.16 (s, 1H), 3.91 (s, 3H), 2.99 (5, 3H); ESI-MS 262 (M−H). Methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylsulfonyl)amino]benzoic acid as a solid, which was used without further purification. ESI-MS 248 (M−H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)C)nc1
Yield: 80 %

Procedure:
As described for example 6f, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (74 mg, 80%), after 1 h instead of overnight, which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1). MS: m/e=353.2 [M+H]+.
Reaction SMILES: C([N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)=[CH:6][CH:5]1[CH3:26])(=O)C.[S]>C1C2C(CCCC2)CCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]2[C:10]([C:7]3[CH:8]=[CH:9][N:4]=[C:5]([CH3:26])[CH:6]=3)=[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nn3cccnc23)=CC1C
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3cccnc23)ccn1
Temperature: 190 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
A mixture of 3-(1-acetyl-1,2-dihydro-2-methylpyridin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine (315 mg) and sulfur (146 mg) in decaline (3 ml) was stirred at 190° C. for 2 hours. The reaction mixture was cooled and purified by column chromatography on silica gel to give 2-(4-fluorophenyl)- 3-(2-methylpyridin-4-yl) pyrazolo[1,5-a]pyrimidine (135 mg) as crystals.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:19][NH2:20]>CC(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:20][CH3:19])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: CN
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CC(C)O
Product: CNc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Yield: 86 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), an aqueous solution of 30% methylamine (4.0 ml) and 2-propanol (20 ml) was stirred in a sealed tube at 100° C. for 4 hours. The reaction mixture was concentrated, and water was added to the resulting residue. The pH was then adjusted 3 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-methylamino-5-oxazolepropionic acid (1.21 g, 86%). This was recrystallized from ethanol to give colorless prisms. mp 217-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccc(Cl)cc5)CC4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NC1CCC(c2ccc(Cl)cc2)CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a suspension of ethyl 6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate (0.065 g, 0.11 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodium hydroxide (0.24 ml, 0.24 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 45 mg of the title compound (73% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([NH:29][C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Product: CCCCNc1nc2c(C(=O)OCC)cnn2c2c1cnc1c2cnn1CC
Reaction time: 8 h
Yield: 83.9 %

Procedure:
3.5 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester (0.01 mol) and 7.3 g of n-butylamine are refluxed together with 30 ml of alcohol with stirring for 8 hours. The solution is evaporated to dryness and the residue treated with water and filtered off. Recrystallization from ethyl acetate yields 3.2 g (84%) of 5-(n-butylamino)-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester; m.p. 275°-277°.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C@@H:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]([F:17])[F:16])[C:10]([OH:12])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:26][C:27]1([C:30]#[N:31])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:30]([C:27]1([NH:26][C:10](=[O:12])[CH:9]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]([F:17])[F:16])[CH2:8][S:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)(=[O:7])=[O:6])[CH2:29][CH2:28]1)#[N:31]
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)N[C@@H](c1ccc(F)cc1)C(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(CS(=O)(=O)CC2CC2)NC(c2ccc(F)cc2)C(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
To a solution of 3-cyclopropylmethylsulfonyl-2(R)-[2,2,-difluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid (0.95 g), 1-aminocyclopropanecarbonitrile HCl salt (400 mg) in DMF (5 mL) at room temperature was added HATU (1.28 g), followed by diisopropylethylamine (1.68 g/2.26 mL). After being stirred at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and brine. The combined organic extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure, and the residue was purified by recrystallization from 2-propanol to yield N-(1-cyano-cyclopropyl)-3-cyclopropylmethanesulfonyl-2-[2,2-difluoro-1-(4-fluorophenyl)ethylamino]-propionamide as colorless crystals (250 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9](=O)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:20]([O:27]S(C(F)(F)F)(=O)=O)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([O:27][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC(=O)C2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a cold solution (−20° C.) of 3.3 g (20 mmol) 7-methoxy-benzofuranone in 30 mL methylene chloride was added 8.3 mL (6.0 mmol) of triethylamine. To the cold mixture, a solution of 8.5 g (30 mmol) of triflic anhydride in 20 ml of methylene chloride was added dropwise. The temperature was kept at −20° C. or 1 hour. The reaction was then quenched with 100 mL of saturated aqueous sodium bicarbonate aand extracted with methylene chloride (2×150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum to give 5.6 g of the desired product. MS (ES) m/z (relative intensity): 265 (M+H,100);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4([CH3:30])[CH2:29][CH2:28]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)=[O:42]>ClCCl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([O:43][C:41](=[O:42])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4([CH3:30])[CH2:29][CH2:28]4)=[O:26])[CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[CH2:15][CH3:16])=[CH:45][CH:46]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CCN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of rac-[(3R,4S)-3-(3,4-dichloro-phenyl)-4-ethylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (25 mg, 0.06 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (10 uL, 0.06 mmol). It was cooled to 0° C. and 4-fluorophenyl chloroformate (8 uL, 0.06 mmol) was added and the reaction mixture was stirred for 30 min at this temperature and then 2 h at ambient temperature. Concentration and purification by chromatography (SiO2, ethyl acetate) afforded the title compound (17 mg, 52%) as a colorless foam. MS m/e: 590.4 [M]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1)=O.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>C(O)CCC>[NH2:18][C:17]1[N:19]=[C:5]([C:7]2[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:16]=1
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(N)n2)n1C
Temperature: 25 °C
Yield: 83.8 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole (Method 15; 2.8 g, 14.5 mmol) and guanidine hydrochloride (3.5 g, 36.3 mmol) were suspended in 1-butanol (30 ml). Sodium methoxide (3.1 g, 58 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The reaction mixture was allowed to cool to ambient temperature and was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 95:5) to give the title compound (2.3 g, 84%). NMR 2.16 (s, 3H), 3.93 (s, 3H) 6.52 (s, 2H), 6.80 (d, 1H), 7.47 (s, 1H), 8.17 (d, 1H); m/z 190.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[S:26][C:27]([N:30]=[C:31]=[O:32])=[CH:28][CH:29]=1.C(Cl)Cl.CO>C(Cl)Cl>[Cl:24][C:25]1[S:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:32])=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccc(Cl)s1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)Nc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (98 mg, 0.307 mmol) was dissolved in 10 ml DCM. TEA (46 mg, 0.45 mmol) was added and the reaction mixture was flushed with Ar. 2-chloro-5-thienylisocyanate (58.8 mg, 0.368 mmol) was added on ice bath, and the resulting mixture was agitated at room temperature overnight. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, low boiling point solvent was evaporated under reduced pressure. Column chromatography (DCM/MeOH=100/1) afforded 87 mg white solid, yield: 59.2%.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[C:10]=1[CH2:36][CH2:37][CH3:38])([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[C:10]([CH2:36][CH2:37][CH3:38])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCc1c(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cccc1OC(C)(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cccc1OC(C)(C)C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-propyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the desired product. Rf=0.22 in 70% ethyl acetate/hexanes; 1H NMR (400 MHz, d6-DMSO) δ7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.6 Hz, 3H), 7.43 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 2H), 6.95 (t, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.24 (d, J=8.4Hz, 1H), 4.13 (t, J=6.4Hz, 2H), 2.87 (t, J=6.4Hz, 2H), 2.41 (t, J=7.6Hz, 2H), 2.32 (s, 3H), 1.40 (s, 6H), 1.23 (sextet, J=7.2 Hz, 2H), 0.71 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.FC1C(F)=C(F)C(F)=C([O:22][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]2[C@@H:37]3[C@@H:32]([NH:33][C:34]([NH:36]3)=[O:35])[CH2:31][S:30]2)=O)C=1>CN(C=O)C>[C:23]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])(=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:37]2[C@@H:32]([NH:33][C:34]([NH:36]2)=[O:35])[CH2:31][S:30]1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2cc(F)c(F)c(F)c2F)N1
Reactant: CC(N)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CC(=O)O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Preparation was accomplished as described by Wilbur [Bioconj. Chem. 1997, 8, 572]. To a 0.13 g (1.3 mmol) quantity of 3-aminobutyric acid dissolved in 20 mL of DMF under argon atmosphere was added 0.4 mL (2.5 mmol) of triethylamine followed by 0.5 g (1.3 mmol) of biotin tetrafluorophenyl ester. The reaction was stirred at 25° C. for 24 h and the solvent was removed under vacuum. The residue was triturated with acetonitrile and filtered. The isolated solid was dried under vacuum to yield 0.5 g (98%) of product as a colorless solid, mp 161-163° C. 1H NMR (DMSO-d6): O 7.6 (m, 1H), 6.2 (d, J=11.2 Hz, 2H), 3.9-4.2 (m, 3H), 2.6 (m, 2H), 2.35 (d, J=12.6 Hz, 1H), 1.7-2.1 (m, 4H), 0.7-1.5 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15](O)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([NH2:23])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 96.7 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10-(1H,9H)-dione (1 g, 3.44 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (0.64 mg, 3.95 mmol) in N,N-dimethylformamide (25 mL) was stirred for 64.5 hours. In one portion, ammonium acetate (0.796 mg, 10.33 mmol) was added, followed by additional N,N-dimethylformamide (15 mL). The solution was stirred for 3.75 hours at room temperature and concentrated in vacuo for 45 minutes. The residue was washed with water (63×20 mL). The insoluble material was filtered and dried to give the title compound (967 mg, 97% yield, m.p. 224-225° C.).