Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S1(CCCC1)(=O)=O.[I-].[Na+].C[Si](C)(C)Cl>O>[C:1]1([N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CCc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Oc1ccc(CCc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A mixture of 38.5 g of the 1-(4-diphenylaminophenyl)-2-(4-methoxyphenyl)ethane prepared in Synthesis Example 1-2, 200 ml of sulfolane, and 45 g of sodium iodide was stirred in a four-neck flask at 120° C. to obtain a solution. The thus obtained solution was cooled to 60° C., and 2 ml of distilled water was added to the solution. 32.6 g of trimethylchlorosilane was then added dropwise to the above solution over a period of 30 minutes. Thus, the reaction was carried out at 60° to 70° C. for three hours. The thus obtained reaction mixture was poured into 500 ml of water, whereby a brown tar was obtained. The thus obtained tar was washed with 200 ml of water several times, and dissolved in 300 ml of toluene, whereby a brown toluene solution was obtained. The thus obtained toluene solution was washed twice with 100 ml of a saturated aqueous solution of sodium sulfite, whereby a transparent toluene solution of light yellow in color was obtained. After the thus obtained transparent toluene solution was dried over anhydrous magnesium sulfate, a solvent was distilled away. The thus obtained product was subjected to chromatography using a silica gel and toluene, whereby 31.4 g of 1-(4-diphenylaminophenyl)-2-(4-hydroxyphenyl)ethane was obtained as an oily material.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[C:12](OCCCC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1(C)C=CC=CC=1>[C:12]([O:10][C@H:3]1[C@H:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][C@@H:1]([CH3:11])[CH2:2]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: CCCCOC(=O)CC(C)=O
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 23 °C
Yield: 114.5 %

Procedure:
A solution of (-)-menthol (23.0 g, 147 mmol, 1 equiv) and 1-butyl acetoacetate (20.0 ml, 121 mmol, 0.80 equiv) in toluene (50 mL) was heated at reflux for 12 h, then was cooled to 23° C. Volatiles were removed in vacuo and toluene (20 mL) and 1-butyl acetoacetate (12.2 mL, 73.5 mmol, 0.50 equiv) were added to the residue. The resulting solution was heated at reflux for 12 h, then was cooled to 23° C. The cooled reaction mixture was concentrated in vacuo and the residue was purified by distillation under reduced pressure (bp 90° C., 30 mmHg) to afford (1R,3R,4S)-p-menth-3-yl acetoacetate (1) as a low-melting solid (33.3 g, 94%). ##STR14##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[Br:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][N:28]([C:19](=[O:21])[C:18]([C:17]1[C:4]3[C:5](=[C:6]([N:9]4[CH:13]=[N:12][C:11]([CH3:14])=[N:10]4)[N:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:15][CH:16]=1)=[O:22])[CH2:29]2
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Brc1cccc2c1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(Br)cccc4C3)c12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A 20 mL vial was charged with 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.1 g, 0.332 mmol), 5-bromo-1,2,3,4-tetrahydroisoquinoline (0.083 g, 0.332 mmol), o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.133 g, 0.415 mmol), Hunig's Base (0.580 mL, 3.32 mmol), and DMF (3 mL). The vial was sealed and stirred at rt. After stirring the mixture for 70.5 h, the reaction was quenched with water. The solids that formed were collected by filtration. The mother liquor was concentrated under reduced pressure, and a second batch of solids was collected by recrystallizing from MeOH and water. The expected product, 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (0.145 g, 0.293 mmol, 88% yield), was isolated as an off-white solid. LC/MS: m/z 495 (M+H)+, 497.02 (M+3H)+1.935 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.42 (s, 1H) 9.22-9.27 (m, 1H) 8.18-8.31 (m, 1H) 7.84 (s, 1H) 7.09-7.59 (m, 3H) 4.59-4.87 (m, 2H) 3.67-3.95 (m, 5H) 2.73-2.96 (m, 2H) 2.47-2.52 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16]CC)=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2
Reactant: CCOC(=O)c1nc2cc(C)c(C)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc2nc(Cl)c(C(=O)O)nc2cc1C

Procedure:
3Chloro-6,7-dimethyl-2-quinoxalinecarboxylic acid, ethyl ester (14.5 g) and sodium carbonate (3.2 g) in methanol (300 ml) and water (75 ml) were heated under reflux for 2 hours. The methanol was distilled off and the aqueous solution was acidified with dilute hydrochloric acid. The solid was collected, dried and crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°). It had m.p. 146.5°-148.5° (d) (75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added ethyl chloroformate (26 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give Ethyl 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidine-1-carboxylate as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.13 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.30-4.26 (m, 2H), 4.14 (q, 2H), 2.99-2.96 (m, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.8-1.77 (m, 2H), 1.64-1.55 (m, 2H), 1.28 (t, 3H); ESMS m/z 488.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].CN1CCOCC1>CO>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: CN(C)CCCN
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCCN(C)C)cc2s1
Yield: 1.7 %

Procedure:
the title compound (2 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N1,N1-dimethylpropane-1,3-diamine (77 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 395.3 (M+1, 100%). Yield=2%.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].[NH2:21][CH2:22][CH2:23][SH:24].C(N(CC)CC)C>C(#N)C>[NH2:21][CH2:22][CH2:23][S:24][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20]
Reactant: NCCS
Reactant: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCc2c(SCCN)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 49.8 %

Procedure:
100 mg of compound (8) obtained in Example 3(1), 56 mg of 2-amino-ethanethiol and 109 mg of triethylamine were added to 2 ml of acetonitrile, and the solution was heated at reflux for 2 hours. After air-cooling, the solvent was removed by distillation. To the residue, ethanol was added, and the deposited solids were filtered off and washed with ether to obtain 60 mg of the subject compound (184).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:22])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
4-(4-Chloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (350 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was concentrated. The white solid was washed with Et2O. After the white solid was treated with 1N NaOH (200 mL) and extracted with Ethyl acetate (3×100 mL), the combined organic phase was dried over Na2SO4 and concentrated to give 17.79 g of desired product (99% yield). 1H-NMR (for HCl salt) (300 MHz, MeOD): δ 2.80-2.90 (m, 4 H), 3.20-3.80 (m, 4 H), 7.29-7.36 (m, 4 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH2:15](I)[CH3:16].Cl>CN(C=O)C.CC(C)=O>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH3:16]
Reactant: CCI
Reactant: OCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOCC1CCC(=O)CC1
Temperature: 25 °C

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-yl)-methanol (from Example 33, 765 mg, 4.44 mmol) in DMF (3 mL) at 0° C. was treated with NaH (Aldrich, 60% in mineral oil, 355 mg, 8.88 mmol) followed by EtI (Aldrich, 0.7 mL, 8.88 mmol). The resulting solution was slowly warmed to room temperature for 2 hours and heated at 60° C. for additional 30 min. The solution was then partitioned between ethyl acetate and saturated NH4Cl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was treated with 1N HCl (2 mL) and acetone (6 mL) at room temperature for 2 hours. The solvent was removed and the solution was then partitioned between ethyl acetate and saturated NaHCO3. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 5:1) to afford the title compound as colorless solid.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][O:17][C:18]([C:20]1[C:21]2[CH:22]=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19].C([O-])(=O)C.[Na+]>C(Cl)CCl>[CH3:16][O:17][C:18]([C:20]1[C:21]2[C:22]([CH:9]=[O:10])=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of N-methylformanilide (15.6 g) and phosphorus oxychloride (17.7 g) is added ethylene dichloride (75 g ) followed by 4-indolecarboxylic acid methyl ester (17.5 g). The reaction mixture is stirred at room temperature for 1 1/2 hr., then at 45°-50°C for 30 minutes more. The mixture is now poured into a solution of 75 g of sodium acetate in 150 ml of ice-water. More ethylene dichloride is added. The layers are separated and the organic phase is washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residual brown oil is passed through a silica gel column using 3% methanol in chloroform. Concentration of the eluate affords a solid which on recrystallization from benzene affords the pure title compound, mp 135°C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]#[N:18].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[CH3:16])=[CH:12][CH:13]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:22][N:23]([CH3:25])[CH3:24])#[N:18]
Reactant: CN(C)c1ccc(Nc2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(Nc2ccc(N(C)C)cc2)c1C#N
Temperature: 30 °C

Procedure:
A suspension of 10 g (41.3 mmol) of 5-amino-4-cyano-3-(4-dimethylamino-phenylamino)-pyrazole [for preparation see: Arch.Pharm.(Weinheim) 326, 245 (1993)] in 8.75 ml (49.5 mmol) of N,N-dimethylformamide diethyl acetal (97%) and 200 ml of toluene is heated under reflux for 1 hour. The reaction mixture is then cooled to approx. 30° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 281-282° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+]>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[NH2:16]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(NN)cc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A solution of 3.725 g (18 mmol) of ethyl 2-(4-aminophenyl)-2-methylpropionate in 18 mL of concentrated hydrochloric acid was stirred at −10 to −5° C. in an ice-acetone bath as a solution of 1.29 g (18.7 mmol) of sodium nitrite in 7.5 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. Next, a small amount of insoluble solid was removed by filtration into a cold receiving flask. The filtrate was then added dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of stannous chloride dihydrate in 14.5 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about −5° C. A gummy material separated during the addition. After completion of the addition, stirring was continued at −10 to −5° C. for 1 hour. The aqueous phase was decanted, and the residual gum was dissolved in 250 mL of ethyl acetate. The ethyl acetate solution was treated cautiously with 250 mL of saturated aqueous sodium bicarbonate solution and shaken in a separatory funnel. The ethyl acetate layer was washed with 50 mL of saturated aqueous sodium chloride solution. The entire mixture was filtered before separation of the phases. The ethyl acetate phase was dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature to yield 2.59 g (65%) of an oil. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure and indicated that only minor impurities were present.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20]N1C(=O)CCC1=O.O[C:29]1[C:30]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:20][C:29]1[C:30]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2C1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2ncnc(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of PPh3 (81.4 g, 310 mmol) and N-chlorosuccinimide (41.4 g, 310 mmol) in dioxane (850 mL) was stirred at ambient temperature for 30 minutes. To this suspension was added tert-butyl 4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and the mixture stirred at 50° C. for 18 hours. The mixture was subsequently treated with triethylamine (25 mL, 183 mmol) and the resulting brown solution concentrated. The black oil was dry packed onto silica gel and purified by chromatography eluting with 15-20% EtOAc/Hexanes to give the title compound as a yellow gum.
Reaction SMILES: C(OC([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]([C@@H:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:25]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:54].C(O)C>ClCCl>[ClH:54].[ClH:54].[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH2:8])=[CH:25][C:26]=1[C@@H:38]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:39][CH2:40][N:41]([CH:45]([CH3:46])[CH3:47])[CH:42]([CH3:44])[CH3:43])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1OCc1ccccc1)C(C)C
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCN)ccc1OCc1ccccc1)C(C)C

Procedure:
Di-tert-butyl(7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenoxy}heptyl)imidodicarbonate (Preparation 17, 220 mg, 0.30 mmol) was dissolved in dichloromethane (6 ml) then hydrogen chloride (2M solution in diethyl ether, 6 ml, 12 mmol) was added and after 30 minutes, ethanol (1 ml) was added and left over night. The solvent was removed in vacuo to furnish the title compound as a pale brown foam, 190 mg.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:4](=[O:6])[C@@H:3]5[CH2:7][CH2:8][CH2:9][N:2]5[CH3:1])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.3 %

Procedure:
A mixture of 1-methyl-L-proline (170 mg, 1.3 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol), 1-hydroxybenzotriazole (175 mg, 1.3 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (490 mg, 1.3 mmol), N,N-diisopropylethylamine (330 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr, and then at 40° C. for 4 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (15 mg, 5%) as a white solid.
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:42])[C@H:20]([C@H:28]1[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:31]([CH3:41])([CH3:40])[CH2:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[O-:43]S([O-])=O.[Na+].[Na+]>C1COCC1.O.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:20]([C@@H:28]2[CH2:29][CH2:30][C:31]([CH3:40])([CH3:41])[N:32]2[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:19]([OH:43])=[O:42])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Br)cc2)CCC1(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
30% H2O2 (0.67 mL, 7.0 mmol) was added to a solution of LiOH—H2O (0.24 g, 5.60 mmol) in THF/water (2:1, 93 mL), and the solution was stirred at room temperature for 10 minutes. The solution was then cooled to 0° C. and treated with a solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-bromophenyl)-2-oxo ethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.60 g, 2.80 mmol) in THF (10 mL). The reaction was stirred at 0° C. for 2 hours and allowed to warm to room temperature and stirred overnight. The reaction was then cooled to 0° C. and treated with 1M Na2SO3 (10 mL) and stirred for 10 minutes. The reaction was then warmed to room temperature and stirred for 10 minutes. The reaction was next concentrated and extracted with EtOAc (2×20 mL). The aqueous layer was then acidified with 1N HCl to a pH of about 1 to about 2 and extracted with DCM (2×20 mL). The combined DCM fractions were dried over sodium sulfate, filtered, and concentrated to give (S)-2-(4-bromophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (1.01 g, 87% yield) as a solid. MS ESI (+) m/z 412 detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:31]=[O:32]>O1CCCC1>[CH2:33]([NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.69 mmol) in tetrahydrofuran (5 mL) and triethyl-amine (0.47 mL, 3.38 mmol) was added isocyanatomethyl-benzene (0.25 mL, 2.03 mmol) dropwise. The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3-benzyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (215 mg, 29%) as a white solid: LC/MS m/e calcd for C26H27N3O3 (M+H)+: 430.52, observed: 430.1.