Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[F:21][C:22]1[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=1)[O:25][CH2:26][C:27]([NH:29]/[C:30](/[CH3:36])=[CH:31]\[C:32](OC)=[O:33])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:32](=[O:33])[CH:31]=[C:30]([CH3:36])[N:29]=[C:27]2[CH2:26][O:25][C:24]2[CH:37]=[CH:38][CH:39]=[C:22]([F:21])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.55 g, 2.80 mmol) in anhydrous CH2Cl2 (40 mL) was added trimethylaluminium (2.0 mL, 4 mmol, 2 M in heptane) carefully under N2 at rt. The mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-(2-(3-fluorophenoxy)acetamido)crotonate (0.75 g, 2.80 mmol) in anhydrous CH2Cl2 (10 mL). The reaction mixture was stirred for another 7 h, then quenched with an appropriate amount of water and washed with brine twice. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (0.24 g, 62%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11].F[C:25]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:13]3[C:22](=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)[O:23][CH2:25]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%): 1H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 2H), 6.87-6.79 (m, 1H), 6.43 (s, 1H), 6.16 (s, 1H), 4.93 (ABq, 2H), 4.22-4.07 (m, 4H), 3.24 (s, 3H); MS (ES+) m/z 387.9 (M+1), 389.9 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:28][C:29]([NH2:31])=[NH:30])=[N:5][CH:4]=1>O1CCOCC1>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:28][C:29]([NH2:31])=[NH:30])=[N:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H]3CC[C@H](C(=O)O)CC3)cc12

Procedure:
A solution of HCl (5 mL, 2 M, 10 mmol) was added to a solution of ethyl trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (55 mg, 0.121 mmol) in dioxane (5.0 mL) and the mixture was heated at reflux for 2 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon MCI gel (CHP 20P) using water-MeOH (100:0 to 20:80) as eluant to give trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-cyclohexanecarboxylic acid. This material was dissolved in dilute HCl (20 mL, 0.1 M), the solvents were evaporated in vacuo, and the residue triturated with Et2O to give trans-4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylic acid hydrochloride (35 mg, 0.067 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:21]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:8][CH:7]=2)[C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1)[CH3:22]
Reactant: CC=O
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.5 g of (RS)-2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol, dissolved in 25 ml of methylene chloride, were treated at 0° C. with 0.46 ml of acetaldehyde and 3.46 g of sodium triacetoxyborohydride, then 0.62 ml of acetic acid was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with the addition of one portion of 25 ml of water and then, was extracted with two portions of 25 ml of methylene chloride. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 25% ethyl acetate/hexanes). 1H NMR (CDCl3): 6.98 (d, J=2.2 Hz, 1H), 6.85 (dd, J=8.4, 2.2 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 3.75-3.55 (m, 2H), 3.33 (q, J=7.1 Hz, 2H), 3.30-3.20 (m, 2H), 2.70-2.55 (m, 1H), 1.80-1.70 (m, 2H), 1.70-1.45 (m, 2H), 1.45-1.20 (m, 6H), 1.26 (s, 6H), 1.14 (t, J=7.1 Hz, 3H), 0.84 (t, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[CH:15][C:9]=2[S:10][C:11]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[CH:15][C:9]=2[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(C(=O)O)sc2ccsc12
Agent: [Cu]
Agent: O=C=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCCCCc1csc2ccsc12
Temperature: 260 °C
Yield: 207.2 %

Procedure:
A mixture of compound 62 (14.6 g, 0.054 mol), copper powder (2.00 g), and quinoline (80 mL) was heated at about 260° C. in a Woods metal bath. When no further bubbles of CO2 were detected (about 2 hours), the mixture was allowed to cool to room temperature, and hexane (200 mL) was added. The mixture was washed repeatedly with HCL (1-2 M in water) to remove the quinoline. The organic layer was dried over MgSO4 and concentrated by evaporation. The residue was purified by column chromatography (SiO2/hexanes) to yield compound 58 (25.1 g, 90.3%). GC/MS: 224 g/mol (M). 1H NMR (CD2Cl2) δ 7.36 (m, 1H), 7.25 (m, 1H), 7.01 (m, 1H), 2.73 (t, 2H), 1.69 (m, 2H), 1.34 (m, 6H), 0.89 (t, 3H). 13C NMR: 140.39, 139.13, 135.39, 127.01, 122.19, 120.26, 32.01, 30.29, 29.43, 23.01, 14.24.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1OCCOCCOCCOCCOCCOC1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44]C2C=NC=CC=2)[CH:39]=1.[K]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:44][C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cncc(Oc2cccnc2)c1
Reactant: COC(=O)c1ccc(CBr)cc1Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
To a solution in toluene (25 mL) of 4-bromomethyl-2-phenoxybenzoic acid methyl ester (3.37 g), prepared as in Example 157E, was added 18-crown-6 (0.52 g) and the potassium 3-pyridyloxide (2.20 g). The reaction mixture was heated at 70° C. for 1 hour during which time a black, insoluble tar formed. The reaction mixture was cooled to ambient temperature and diluted with toluene. The toluene was decanted from the tar and the tar was dissolved in 1:1 THF-water (20 mL). The aqueous THF was added to the toluene and the mixture was washed twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a black oil. Chromatography on silica gel (1:1 ethyl acetate-hexanes) gave 4-(3-pyridyloxymethyl)-2-phenoxybenzoic acid methyl ester (2.47 g).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])=[CH:8][CH:7]=1.OC1C=CC(CCNC(=O)CN[C:32](=[O:63])[C@H:33]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:34][C:35](=[O:58])[C@H:36]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[NH:37][C:38](=[O:50])[CH2:39][NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)=CC=1.[OH-].[Na+].Cl[CH2:68][CH:69]1[CH2:71][O:70]1.[OH-].C1(C[N+](C)(C)C)C=CC=CC=1>O.CO>[O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][C:32](=[O:63])[C@H:33]([CH2:59][CH:60]([CH3:61])[CH3:62])[NH:34][C:35](=[O:58])[C@H:36]([CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:37][C:38](=[O:50])[CH2:39][NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:68][CH:69]3[CH2:71][O:70]3)=[CH:44][CH:43]=2)=[CH:10][CH:11]=1
Reactant: NCC(=O)NCCc1ccc(OCC2CO2)cc1
Reactant: ClCC1CO1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)c1ccc(O)cc1)C(=O)NCC(=O)NCCc1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)c1ccc(OCC2CO2)cc1)C(=O)NCC(=O)NCCc1ccc(OCC2CO2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
N-(N-(N-(N-(4-(Oxlranylmethoxy)benzoyl)glycyl) phenylalanyl) leucyl) glycine N-(2-(4-(oxiranylmethoxy)phenyl)ethyl)amide. N-(N-(N-(N-(4-Hydroxybenzoyl)-glycyl)phenylalanyl)leucyl)glycine N-(2-(4-hydroxyphenyl) ethyl)amide (106 mg, 0.131 mol) was suspended in water (12 mL) containing sodium hydroxide (52.3 mg, 1.31 mmol). Chloromethyloxirane (604 mg, 6.5 mmol) in methanol (10 mL) was added, followed by phenylmethyltrimethylammonium hydroxide (40% aqueous solution, 90 mg). The solution was stirred for 48 h at 40° C. The solvent and excess reagent were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and was washed with water. The solution was dried with anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure. Column chromatography (silica gel; ethyl acetate, then ethyl acetate/methanol 39:1, then ethyl acetate/methanol 19:1, then ethyl acetate/methanol 9:1) gave N-(N-(N-(N-(4-(oxiranylmethoxy)benzoyl)glycyl)phenylalanyl)leucyl)glycine N-(2-(4-(oxiranyl-methoxy)phenyl)ethyl)amide (26.5 mg, 27%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:35]=[C:36]=[O:37])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:36]([NH:35][C:27]4[CH:26]=[C:25]([O:24][CH3:23])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=4)=[O:37])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)NC2C=CC(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a stirred solution of 5-(4amino-cyclopent-2-enyl)9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (69 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added 3,4,5-trimethoxy-isocyanato benzene (55 mg, 0.26 mmol) and DMAP (catalytic amount) and stirred at rt. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (116 mg, 100%). Mass Spectrum (FIA) (m/z) 425.3 (M+1) 1H NMR (CDCl3): δ 7.45 (d, 1H); 7.40 (t, 1H); 7.33 (d, 1H); 6.58 (m, 3H); 5.95 (m, 1H); 5.83 (m, 1H); 5.18 (s, 1H); 3.78 (s, 9H); 2.98 (m, 2H); 2.05 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:15]1(=[O:25])[O:20][C:18](=[O:19])[C@H:17]2[CH2:21][CH:22]=[CH:23][CH2:24][C@@H:16]12>ClCCCl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:15]([CH:16]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:21][CH:22]=[CH:23][CH2:24]1)=[O:25])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccccc2c1C(=O)C1CC=CCC1C(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
2-Methyl indole (50 mmol, 6.55 g) and AlCl3 (50 mmol, 7.3 g) were stirred in 500 mL DCE. cis-1,2,3,6-Tetrahydrophthalic anhydride (50 mmol, 7.6 g) was added and the reaction was heated to 65° C. for 6 h. The reaction was carefully quenched with 10 mL water and stirred overnight. The resulting red solid was filtered, washed with water, and dried to give 15 g of the sub-title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:16][CH2:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:21]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a stirred solution of ethyl acrylate (141 g, 1.41 mole) and N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (Compound D17 of EP 0363085, 435 g, containing approximately 75% of D17, 1.4 moles) in dichloromethane (2.5L) at -5° C. was added trifluoroacetic acid (16.1 g, 0.14 mole) in dichloromethane (100 ml) ensuring that the temperature did not rise above 0° C. This mixture was then transferred by cannula to stirred, refluxing dichloromethane (50 ml) over 40 minutes at such a rate as to maintain gentle reflux. The reaction mixture was then refluxed for a further 1h before cooling to room temperature. It was then washed with saturated aqueous potassium carbonate, dried (Na2SO4), and concentrated in vacuo to a gum which was distilled to afford the title compound (D1) as a clear oil (286 g, 88%) b.p. 120°-150° C. at 4 mmHg.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4](=[O:18])[CH2:3]1.[H-].[Na+].[C:21]([S:24][CH2:25]CBr)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([S:24][CH2:25][C:3]1([CH2:25][S:24][C:21](=[O:23])[CH3:22])[C:2](=[O:1])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[N:5]2[C:4]1=[O:18])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CC(=O)N12
Reactant: CC(=O)SCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SCC1(CSC(C)=O)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
(c) A solution of 1.27 g of tert.butyl hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxyate in 10 ml of dimethylformamide was added to a suspension of 0.4 g of sodium hydride in dimethyformamide. The mixture was stirred at room temperature until the evolution of gas had ceased. 1.86 g of S-bromoethyl thioacetate were added and the mixture was heated at 75° C. for 5 hours. Working-up in the same manner as described in paragraph (D) (a) earlier gave 0.15 g (7%) of tert.butyl 2,2- bis(acetylthiomethyl)-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 85°-86° C. (from diethyl ether/hexane).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][O:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][NH:11][C:12](=O)[O:13]C1C=CC=CC=1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]([F:34])([F:35])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[CH2:6][O:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][NH:11][C:12](=[O:13])[NH:36][CH:37]1[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Yield: 72.1 %

Procedure:
Compound 84 produced in Example 77 (0.85 g, 1.7 mmol), tert-butyl 4-aminopiperidin-1-carboxylate (0.34 g, 1.7 mmol) and triethylamine (0.28 mL, 2.0 mmol) were dissolved in isopropyl alcohol and heated to reflux for 20 hours. After the solvent was evaporated therefrom in vacuo, the residue was purified by a column chromatography (toluene:acetone=4:1) to give Compound 85 (0.74 g, 72%).
Reaction SMILES: C(S[C:9]1[C:10]([Cl:22])=[C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[S:23]([Cl:27])(Cl)(=[O:25])=[O:24]>>[Cl:22][C:10]1[C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])=[CH:12][CH:13]=[CH:14][C:9]=1[S:23]([Cl:27])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1COCCN1c1cccc(SCc2ccccc2)c1Cl
Product: O=C1COCCN1c1cccc(S(=O)(=O)Cl)c1Cl

Procedure:
Intermediate 17 (1 g, 3.05 mmol) was converted to the title sulfonyl chloride using the procedure described in 1.7). The crude material was used without further purification in the next step.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccc2nonc12
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2)Nc2n[nH]cc2C1c1cccc2nonc12

Procedure:
The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.
Reaction SMILES: C(O[C@@H](C)CCCC[N:10]1[C:19](=[O:20])[C:18]2[N:17](CC3C=CC=CC=3)[C:16](CO)=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=O)C>S(Cl)(Cl)=O>[CH3:30][N:13]1[C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19](=[O:20])[NH:10][C:11]1=[O:12]
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(CO)n2Cc2ccccc2)n(C)c1=O
Solvent: O=S(Cl)Cl
Product: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 228.7 %

Procedure:
To a solution of thionyl chloride (100 ml) was added (S)-1-(5-acetoxyhexyl)-7-benzyl-8-hydroxymethyl-3-methylxanthine (9.8 g, 22.9 mmol). After stirring for 3 hours at room temperature, unreacted thionyl chloride was evaporated under reduced pressure. The residual oil was purled by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to afford (S)-1-(5-acetoxyhexyl)-7-benzyl-8-chloromethyl(-3-methylxanthine (8.7 g, 85% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=O)=[O:10].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[S:9]([CH3:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of (2,4-dichloro-phenyl)-methyl sulfone (Ono Mitsunori, Nakamura Yoshisada, Sato Shingo, Itoh Isamu, Chem. Lett, 1988, 395–398.; 3.33 g, 16 mmol) and sulfuric acid (conc, 14 ml) was added a mixture of sulfuric acid (4 ml) and nitric acid (fuming, 2 ml) dropwise under ice-water bath. The mixture was stirred at 55° C. for 1 h. The mixture was poured onto ice-water and neutralized with 6N aqueous NaOH and then extracted with dichloromethane. The organic layer was washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with hexane/ethyl acetate (2:1/1:1) to give 3 g (74%) of the title compound as white solids.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]5[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=5)=[O:33])=[CH:27][C:26]=4[N+:41]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>[Fe].C(O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]5[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=5)=[O:33])=[CH:27][C:26]=4[NH2:41])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(NC(=O)c3ccc(Br)cn3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(NC(=O)c2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 100 °C

Procedure:
The product from Example 384C (0.20 gm, 0.30 mmol) was suspended in a 4/1 v-v mixture of glacial acetic acid and ethanol (8 ml). To this vigorously stirred suspension was added, in one portion, iron powder (0.215 gm, 3.85 mmol) and the resulting mixture heated under nitrogen in an oil bath at 100° C. After 19.5 hours the reaction mixture was cooled then concentrated under vacuum to a paste which was suspended in water and the solid product collected by vacuum filtration. The cake was washed with water then dried in vacuo at room temperature (0.204 gm, quant.).
Reaction SMILES: C[N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[C:6](=[O:17])[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[F:24]C1C=CC(N)=CC=1.CCCCCCC>C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:2][C:3]([C:5]2[C:6](=[O:17])[N:7]([CH3:16])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:4])=[CH:19][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CN(C(=O)c1c(O)c2ccccc2n(C)c1=O)c1ccccc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C(=O)Nc2ccc(F)cc2)c(O)c2ccccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (15 mg, 0.050 mmol) and 4-fluoro-aniline (0.100 mmol) in toluene (0.5 mL) was stirred at 100° C. for 1 h. Heptane (1.5 mL) was added and the solution was allowed to cool to room temperature. The crystallized product was separated from the solution and washed with heptane to give the title compound (12 mg, 79%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:35])[CH:5]([N:20](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:6][N:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(OC(C)C)(=O)C>[CH3:2][O:3][C:4](=[O:35])[CH:5]([NH2:20])[CH2:6][N:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[N:9]=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: COC(=O)C(CN(c1ccccc1)c1ncccn1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: COC(=O)C(N)CN(c1ccccc1)c1ncccn1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
470 ml of 5N hydrochloric acid were added dropwise to a solution of 100 g (212 mmol) of 2-[bis-(tert-butoxycarbonyl)]amino-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester in 1000 ml of isopropyl acetate at 15° C., and the mixture was stirred for 2 h. Then the phases were separated and the pH of the aqueous phase was adjusted to 8.5 by addition of an aqueous solution of ammonia under cooling in an ice bath. The aqueous phase was extracted with ethyl acetate, and the extract washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo to give 52.8 g (92%) of 2-amino-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester as a yellow oil.