Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Cl:20]N1C(=O)CCC1=O>C1COCC1>[Cl:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Cl)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 18.7 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.10 g, 0.38 mmol) in THF (5 mL) in a microwave reaction tube was added N-chlorosuccinimide (0.046 g, 0.42 mmol). The mixture was heated at 70° C. in a microwave oven for 20 min After cooling to room temperature, it was purified using preparative LCMS to provide the product (0.021 g). 1HNMR (300 MHz, CD3OD): δ 4.39 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 1.91 (m, 2H), 1.39 (m, 4H), 0.92 (m, 3H). LCMS calculated for C12H16ClN6O (M+H): 295.1. Found: 295.1.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:23][C:21]1[CH:20]=[CH:19][C:3]2[N:4]([CH:7]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]3)[CH2:5][CH2:6][S:1][C:2]=2[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccccc32)C1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(Br)ccc32)C1
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A solution of tert-butyl 3-(2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.41 g, 1.302 mmol) in DMF (5 mL), was cooled to 0° C. and treated dropwise with N-bromosuccinimide (0.17 g, 0.977 mmol) in DMF (5 mL) for 15 minutes. The reaction was kept at 0° C. and was stirred for 1 hour at this temperature. At this time, N-bromosuccinimide (0.023 g, 0.130 mmol) in DMF (1 mL) was added dropwise to the reaction, which was then stirred for 1 hour at 0° C. The solution was treated again with N-bromosuccinimide (0.023 g, 0.130 mmol) in DMF (1 mL) and was stirred for 1 hour at 0° C. The solution was diluted in water (100 mL) and extracted with EtOAc (2×100 mL). The aqueous phase was washed once with EtOAc (50 mL). The organic solutions were combined, washed with water (100 mL) and brine (50 mL), and dried (Na2SO4). The crude material was filtered through a silica pad (20% EtOAc/hexanes) and concentrated to give clear oil (0.47 g, 90%). 1H NMR (CDCl3) δ 7.18 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 4.34-4.28 (m, 1H), 3.71-3.23 (m, 6H), 3.03-3.04 (m, 2H), 2.19-1.95 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 423, 421 (M+Na, 8), 401, 399 (MH+, 2), 343, 345 (100).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCCCO
Product: CCCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and n-butanol there is obtained butyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 1.02 (t, CH2CH3), 1.4-2.0 (4H), 4.15 (t, OCH2), 4.27 (s, 4H), 4.57 (broad s, NH), 7.3-7.7 (8H);
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CCC>C(Cl)Cl.O>[C:12]([O:11][C:9]([NH:8][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[C:6]([OH:23])=[O:5])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1O

Procedure:
Similarly, N-t-butoxycarbonyl-2-(2-hydroxyphenyl)-glycine n-butyl ester was hydrolyzed to give N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine, m.p. 125° (methylene chloride-water).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH:19]C=O)=[N:13][C:14]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:25](O)(=[O:27])C>CO>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([O:27][CH3:25])[N:13]=1
Reactant: O=CNc1nc(Cl)c2ncn(OCc3ccccc3)c2n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2OCc1ccccc1
Yield: 76 %

Procedure:
A mixture of 9-benzyloxy-6-chloro-2-formamidopurine (440mg, 1.60mmol), 1.2M sodium methoxide in methanol (5.3ml) and methanol (10ml) was heated at reflux temperature for 1 hour and then cooled. Acetic acid (4ml) was added and the solution evaporated to dryness. The residue was suspended in water and extracted with chloroform (2×25ml). The combined chloroform extracts were washed with brine, dried (magnesium sulphate) and evaporated under reduced pressure. Column chromatography on silica gel (eluted with chloroform-methanol, 100:1) afforded the title compound (331mg, 76%). IR: υmax (KBr) 3480, 3310, 1625, 1585, 1505, 1485, 1460, 1400cm-1 ; 1H NMR: δH [(CD3)2SO] 3.96 (3H, s, CH3), 5.31 (2H, s, CH2Ph), 6.64 (2H, br.s, D2O exchangeable, NH2), 7.42 (5H, s, Ph), 7.75 (1H, s, H-8). Found: C, 57.18, H, 4.84; N, 25.85%). m/e 271.1075. C13H13N5O2 requires: C, 57.56, H, 4.83, N, 25.82%; m/e 271.1069.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1=CNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.2 g (35 mmol) of 4-formylbenzoic acid was dissolved in 100 ml of dichloromethane. 2.0 g (29 mmol) of pyrroline, 5.9 g (35 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 6.1 ml (43 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 5 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[C:24]([CH:26]=[O:27])[N:23]=[CH:22]1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([N:21]1[CH:25]=[C:24]([CH:26]=[O:27])[N:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trityl chloride (9.5 g, 34.3 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to an ice-cooled solution of imidazole-4-carboxaldehyde (3 g, 31.2 mmol) and triethylamine (17 ml, 125 mmol) in N,N-dimethylformamide (30 ml) and the solution was stirred for 2 hours. The reaction was then allowed to warm to room temperature, and was stirred for a further 18 hours. Water (200 ml) was added, and the resulting pink solid was collected and dried, then dissolved in dichloromethane (200 ml). The resulting solution was washed with water (2×100 ml), dried (MgSO4) and evaporated under reduced pressure. The product was recrystallised from ethanol to afford the title compound as a solid, 7.8 g. 1H-NMR (CDCl3, 400 MHz) δ: 7.06 (m, 6H), 7.32 (m, 9H), 7.48 (s, 1H), 7.58 (s, 1H), 9.82 (s, 1H). Microanalysis found: C, 81.54; H, 5.37; N, 8.24. C23H1BN2O requires C, 81.63; H, 5.36; N, 8.28%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)[CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:33][CH2:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24]([NH:33][CH2:34][C:35]3[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=3[C:37]([O:39][CH3:40])=[O:38])=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:28])[F:29])=[N:20]2)[CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Reactant: COC(=O)c1ccccc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Yield: 61 %

Procedure:
A solution of acid 7 (preparation described in scheme 2, example 1c, step 7) (140 mg, 0.303 mmol), methyl 2-(aminomethyl)benzoate hydrochloride (61.0 mg, 0.303 mmol), BOP (134 mg, 0.303 mmol) and triethylamine (0.127 mL, 0.908 mmol) in DMF (2 mL) was shaken for 16 hours at room temperature. It was then diluted with water (˜30 mL) and extracted into ethyl acetate (3×). The ethyl acetate was combined and washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography using a 25S Biotage column with a gradient of 40-65% ethyl acetate in hexanes to give compound 15f (112.7 mg, 61.1% yield) as a white crusty solid. LRMS (ESI): calc. 609.2; found 632.1 (MNa)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]12[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:14](=[O:23])[N:9]1[CH2:10][CH2:11][NH:12][CH2:13]2.O.[C:25]([OH:34])(=[O:33])[C@H:26]([C@@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C@:8]12[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:14](=[O:23])[N:9]1[CH2:10][CH2:11][NH:12][CH2:13]2.[C:30]([C@H:28]([C@@H:26]([C:25]([O-:34])=[O:33])[OH:27])[OH:29])([O-:32])=[O:31]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: O=C1N(CC(F)(F)F)C(=O)C2(Cc3ccccn3)CNCCN12
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Product: O=C1N(CC(F)(F)F)C(=O)[C@]2(Cc3ccccn3)CNCCN12
Temperature: 56 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of 8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione (prepared according to the method described in Step 6, 106 g, 0.325 mol) in acetone (2120 mL) and water (212 mL) was added D-tartaric acid (48.46 g, 0.325 mol). White precipitate formed and it was granulated for 3 hours. The solids were collected by suction filtration and washed with acetone. The solvent damp solids were placed in acetone (1000 mL) and stirred at 56° C. overnight. The solids were collected by suction filtration the next morning and dried to give 56 g of the chiral title compound as the D-tartrate salt (73% yield of theory). Chiral HPLC showed an optical purity of 98:2.
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1>C(OCC)C>[CH3:1][N:2]1[C:10](=[O:11])[C:7]2[C:6](=[CH:5][CH:4]=[CH:9][CH:8]=2)[C:4]21[CH2:9][CH2:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH2:5]2
Reactant: CN
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCOCC
Product: CCOC(=O)C1=CCC2(CC1)c1ccccc1C(=O)N2C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 44 %

Procedure:
A 40% methanolic solution (20.0 mL) of methylamine was added to a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g) in diethyl ether (100 mL) and stirred at room temperature for 5.5 hours. Drylite (10.0 g) was added thereto followed by stirring at room temperature for 18 hours. After it was filtered, the filtrate was concentrated. The resulting residue was dissolved in toluene (100 mL), then triethylamine (8.20 mL) and 2-iodobenzoyl chloride (10.97 g) were added thereto and the mixture was stirred for 2 days at 80° C. in a nitrogen atmosphere. A saturated sodium bicarbonate solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. It was purified by a silica gel column chromatography (hexane/ethyl acetate=9/1→3/1). The resulting residue was dissolved in acetonitrile (200 mL), then potassium carbonate (10.70 g), tetraethylammonium chloride (6.42 g), triphenylphosphine (2.03 g) and palladium acetate (869 mg) were added thereto and the mixture was stirred for 17 hours at 80° C. in a nitrogen atmosphere. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. It was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1→3/2). The resulting solid was suspended in diisopropyl ether and filtered to give the aimed compound (7.36 g, 44%) as a light yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[CH3:48][C:49]1[S:50][C:51]([CH:60]([NH2:68])[CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:53]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:68][CH:60]([C:51]1[S:50][C:49]([CH3:48])=[N:53][C:52]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:38]
Reactant: Cc1nc(-c2ccccc2)c(C(N)Cc2ccccc2)s1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(C(Cc2ccccc2)NC(=O)Cc2c[nH]c3ccc(O)cc23)s1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 15B (29.4 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.59 (d, J=7.6 Hz, 1H), 7.44-7.22 (m, 5H), 7.07 (dd, J=5.5, 3.2 Hz, 4H), 6.92 (dd, J=6.5, 2.9 Hz, 3H), 6.80 (d, J=2.2 Hz, 1H), 6.55 (dd, J=8.6, 2.3 Hz, 1H), 5.34 (dd, J=15.0, 7.5 Hz, 1H), 3.36 (s, 2H), 3.07 (dd, J=13.8, 7.9 Hz, 1H), 2.84 (dd, J=13.5, 7.0 Hz, 1H), 2.60 (s, 3H); MS (m/z) 468 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]([CH3:11])[C:7](=[N:9][OH:10])[CH3:8])=[O:4].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C.C(Cl)Cl>[C:20]1([NH:26][C:27]([O:10][N:9]=[C:7]([CH:6]([N:5]([C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:11])[CH3:8])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=NO)C(C)N(C(=O)CCl)c1c(C)cccc1C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=NOC(=O)Nc1ccccc1)C(C)N(C(=O)CCl)c1c(C)cccc1C

Procedure:
Following the procedure of Example 11, 3 g of 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone oxime, 3 g phenylisocyanate and 5 drops triethylamine in 100 ml methylene chloride were stirred, refluxed and worked up to yield the title product, m.p. 115°-117° C. This product is tabulated as Compound No. 18 in Table I.
Reaction SMILES: [C:1](=[N:10][OH:11])([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].[CH2:12]([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[Br-:19].[CH2:12]([N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[N:10][OH:11])[CH2:2][CH3:3])[CH2:5]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=NO)c1cccnc1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(=NO)C1=CC=CN(Cc2ccccc2)C1
Product: [Br-]

Procedure:
A mixture of 17.8 g of 3-propionyl pyridine oxime [(U.S. Pat. No. 3,004,979 (1961)] and 18 cm3 of benzyl bromide is maintained at reflux for 7 hours 30 minutes in 250 cm3 of ethyl acetate. After cooling and separating, 36.5 g of the expected product is obtained. m.p. 178°-180° C., recrystallized from an ethanol-ether mixture.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:23]([OH:24])[C@H:22]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([O:46]CC3C=CC=CC=3)[C@@H:36]([O:37]CC3C=CC=CC=3)[C@@H:27]2[O:28]CC2C=CC=CC=2)[C@@H:21]([CH2:57][OH:58])[O:20][C@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([NH:4][C@@H:5]1[C@@H:23]([OH:24])[C@H:22]([O:25][C@@H:26]2[O:55][C@@H:54]([CH3:56])[C@@H:45]([OH:46])[C@@H:36]([OH:37])[C@@H:27]2[OH:28])[C@@H:21]([CH2:57][OH:58])[O:20][C@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@H](O)[C@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H]1NC(C)=O
Reaction time: 24 h
Yield: 85 %

Procedure:
The syrupy product was used directly for the preparation of 8-methoxycarbonyloctyl 2-acetamido-4-O-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)-2-deoxy-β-D-glucopyranoside. The crude disaccharide (3.78 g) was dissolved in 50 ml of dry methanol, and 5 ml of 0.2 N sodium methoxide in methanol was added. After 24 h at room temperature, the solution was deionized using the acid resin. Solvent removal left an oil which was dissolved in dichloromethane (100 ml). The solution was washed with water and dried over magnesium sulfate prior to evaporation to a residue (1.01 g, 85% yield) from the fully blocked disaccharide. Purification was by recyrstallization from ethyl acetate-hexane, mp 145°-146°, [α]D25 - 33.6° (c 1.2, chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=2)[OH:20])[CH3:16])=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.I.[NH2:41][C:42]1[C:43]([C:50]([NH:52][C:53](=[NH:56])SC)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1>C(O)C>[NH2:41][C:42]1[C:43]([C:50]([N:52]=[C:53]([NH2:56])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([NH:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([NH:27][CH:28]=[O:29])[CH:26]=3)[OH:20])[CH3:16])=[CH:10][CH:11]=2)=[O:51])=[N:44][C:45]([Cl:49])=[C:46]([NH2:48])[N:47]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A solution composed of compound 28 (0.10 g, 0.25 mmol), Hunig's base (0.21 mL, 1.23 mmol) and ethanol (5 mL) was heated at 70° C. for 30 min before 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (0.11 g, 0.27 mmol) was added. The resulting solution was continuously stirred at that temperature for an additional 3 h before it was cooled to room temperature. The solvent was removed by evaporation. The resulting residue was subjected to column chromatography eluting with a mixture of methanol (0-28%), concentrated ammonium hydroxide (0-2.8%) and dichloromethane (100-69.2%) to afford 30 (87 mg, 56%) as a yellow solid: m.p. 120-121° C. (decomposed); [α]D25 −6.65° (c 0.20, methanol); 1H NMR (500 MHz, DMSO-d6) δ 1.08 (d, 3H), 1.32 (m, 2H), 1.48-1.72 (m, 6H), 2.55 (m, 4H), 2.64-2.92 (m, 3H), 3.16 (m, 2H), 4.56 (m, 1H), 6.76 (m, 1H), 6.82 (m, 1H), 6.92 (m, 1H), 7.10 (m, 4H), 8.07 (s, 1H), 8.28 (s, 1H), 8.51 (s, 1H), 9.30 (s, 1H), 9.59 (s 1H); m/z (ESI) 626 [C30H40ClN9O4+H]+.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][N:15]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][NH:17][C:16]2=[S:24])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:28][CH2:29][CH3:30].[CH2:31](O)C>>[CH2:2]([O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][N:15]2[C:19]([C:20]([O:22][CH2:23][CH3:31])=[O:21])=[CH:18][N:17]=[C:16]2[S:24][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COC(=O)c1c[nH]c(=S)n1Cc1ccc(OCc2ccccc2)cc1
Reactant: CCO
Agent: [Na]
Product: CCCSc1ncc(C(=O)OCC)n1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To 60 mL of ethanol at 25° was added portionwise 0.30 g of sodium metal. After the sodium metal has reacted 3.54 g of 1-(4-benzyloxybenzyl)-5-carbomethoxy-2-(3H)-imidazolethione was added followed immediately by 2.24 mL of 1-iodopropane, and the mixture was stirred at 24° for 3 hours. At this point, the solvent was removed in vacuo, and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to furnish 3.46 g of crude 1-(4-benzyloxybenzyl)-2-propylthio-5-carboethoxyimidazole, used in a subsequent reaction without further purification; NMR (200 MHz, CDCl3): δ 7.77 (s, 1 h); 7.45-7.32 (m, 5H); 7.03 (A2B2, 4H); 5.49 (s, 2H); 5.03 (s, 2H); 4.28 (quart., 2H); 3.20 (t, 2H); 1.32 (t, 3H); 1.02 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(C)=O)ncc1Cl

Procedure:
2-[2-(1-Acetyl-4-oxo-1,2,3,4,5,6-hexahydro-benzo[b][1,5]diazocin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Isolated as a beige solid. MP: 97-103. HPLC purity: 95%, LCMS: 512.28 (M+H)HNMR: CD3OD: 8.16 (s, 1H), 7.51-7.41 (m, 5H), 7.12 (d, J=8.6 Hz, 1H), 4.79-4.75 (m, 1H), 4.37-4.33 (m, 1H), 3.86-3.79 (m, 1H), 3.20-3.12 (m, 1H), 2.86 (s, 3H), 2.73-2.71 (m, 1H), 2.49-2.44 (m, 1H), 1.78 (s, 3H).