Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[Br:32].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Br:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([NH:22][C:8]([C:7]3[CH:6]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)[CH2:5][C:4](=[O:21])[NH:3][C:2]=3[CH3:1])=[O:9])[CH:24]=2)[NH:28][N:27]=1
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
The product of Example 1, Step 2 (115 mg, 0.409 mmol, 1.00 equiv), 5-amino-3-bromoindazole (87 mg, 0.409 mmol, 1.0 equiv), and EDC (94 mg, 0.491 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.068 mL, 0.491 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 47 mg (24%) of the title compound as an off white solid. MS (ES+) m/e 476 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O>C(O)C(C)C>[CH2:1]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:16][CH:17]=1)=[O:3])[CH:4]([CH3:17])[CH3:5]
Reactant: O=C(O)c1ccc(Cc2ccccc2O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)CO
Solvent: O
Product: CC(C)COC(=O)c1ccc(Cc2ccccc2O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2-(4-Carboxybenzyl)phenol (603 mg) was dissolved in isobutanol (3 ml), added with sulfuric acid (0.6 ml) and stirred at 80° C. for 3 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=5:1) to obtain 318 mg of the title compound. Yield: 42%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:14]=O>C(O)C.ClCCl.[Pd]>[NH2:14][C:3]1[C:4]([CH3:13])=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:2]=1[NH2:1]
Reactant: Cc1nn(-c2ccccn2)c(N)c1N=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1nn(-c2ccccn2)c(N)c1N
Yield: 99.4 %

Procedure:
By the method of Preparation 8(b), 5-amino-3-methyl-4-nitroso-1-(2-pyridyl)pyrazole (1.37 g, 6.75 mmol) in ethanol/dichloromethane=4:1 (50 ml) was hydrogenated over 10% palladium on carbon at 20 p.s.i. to give the title compound (1.27 g, 100%).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[SH:19][CH2:20][CH2:21][OH:22]>CN(C=O)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:2]=1[S:19][CH2:20][CH2:21][OH:22]
Reactant: OCCS
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc([N+](=O)[O-])c(F)cc1SCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred suspension of 2,4-difluoro-5-nitroaniline (100 mg, 0.574 mmol) and potassium carbonate (159 mg, 1.149 mmol) in DMF (1 mL) was added 2-mercaptoethanol (0.081 mL, 1.149 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed (1:1 EtOAc:hexanes) to give the major product. Ethyl acetate was then used as the eluent to give a minor product. The major product was determined to be the desired product (112 mg, 84%). 1H NMR (DMSO-d6) δ 7.32 (d, J=3.5 Hz, 1H), 7.27 (d, J=10.7 Hz, 1H), 4.39 (s, 2H), 3.85-3.76 (m, 2H), 3.16-3.08 (m, 2H), 2.13-2.05 (m, 1H); ESI-MS (m/z, %): 233 (MH+, 100), 215 (14), 187 (100), 129 (65).
Reaction SMILES: [CH3:1][O:2][NH+:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[S:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CO[NH+]=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csnn1
Yield: 61.6 %

Procedure:
2-Methoxyiminio-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1.0 g.) and 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.16 g.) were reacted according to similar manners to those of Examples 1(b) and 8 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.68 g.), mp 104° to 115° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([C:7]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][C:4]=2[N:8]=1)[CH3:10]
Reactant: OB(O)c1ccccc1
Reactant: CCc1nc2cc(Br)ccc2n1-c1ccc(CCO)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1nc2cc(-c3ccccc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 95 °C
Reaction time: 11 h
Yield: 26.6 %

Procedure:
To a solution of 2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4, 116 mg, 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 ml) was added PhB(OH)2 (141 mg, 1.16 mmol), K2CO3 (240 mg, 1.75 mmol) and Pd(PPh3)4 (67 mg, 0.06 mmol). This mixture was stirred at 95° C. for 11 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (4×10 ml). The organic layer was dried (MgSO4) and concentrated to give brown oil. This mixture was purified by SiO2 preparative TLC (hexane/ethyl acetate=1/5) to afford 52 mg (27%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH2:24]2)[C:20](=[O:39])[NH:19][C:18]2([C:40]([NH:42][S:43]([CH:46]3[CH2:48][CH2:47]3)(=[O:45])=[O:44])=[O:41])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:50].O1CCOCC1>>[ClH:50].[ClH:50].[NH2:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH2:24]2)[C:20](=[O:39])[NH:19][C:18]2([C:40]([NH:42][S:43]([CH:46]3[CH2:47][CH2:48]3)(=[O:44])=[O:45])=[O:41])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 92 %

Procedure:
A stirred slurry of [4-cyclopropane-sulfonylaminocarbonyl-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester (1.20 g, 1.7 mmol) was treated with 4N HCl/dioxane (Aldrich)(10 mL) for 4 h. The reaction mixture was concentrated in vacuo to give 1.10 g (92%) of cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride as a white solid: LC-MS (Method B, retention time: 1.39 min), MS m/z 596 (M++1–2HCl).
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:18]([NH2:21])[CH2:19][CH3:20]>O1CCCC1>[Cl:17][C:12]1[C:11](/[C:2](/[NH:21][CH2:18][CH2:19][CH3:20])=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCCN
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Solvent: C1CCOC1
Product: CCCN/C(=C(/C#N)C(=O)OCC)c1cccnc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of ethyl 3-chloro-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.3 g, 1.10 mmol, 1 eq.) in 5 ml of tetrahydrofuran was added propylamine (0.131 g, 2.21 mmol, 2 eq.) at room temperature. After being stirred for 8 h at 80° C., the mixture was evaporated. The residue was diluted with AcOEt and the precipitate was filtered off. The filtrate was evaporated and the residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-2-cyano-3-(propylamino)acrylate (0.240 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1>[CH2:13]([NH:15][C:16]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1)=[O:17])[CH3:14]
Reactant: CCN=C=O
Reactant: Cc1cc2sc(N)nc2cc1O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(O)c(C)cc2s1
Temperature: 62.5 °C
Yield: 60.9 %

Procedure:
To the solution of 2-amino-6-methyl-benzothiazol-5-ol (0.20 g, 1.11 mmol) in 1,4-dioxane (5 mL) was added ethylisocyanate (0.13 mL, 1.68 mmol) at room temperature. The resulting mixture was heated to 60-65° C. for 16 h. After completion of reaction (TLC monitoring), 1,4-dioxane was distilled off and co-evaporated with hexane (twice). The solid residue was treated with water to 60-70° C. for 2-4 h. The resulting solid was filtered off and dried under vacuum to obtain the white solid compound (0.17 g, 61%). 1H NMR (DMSO-d6, 400 MHz): δ 1.07 (t, J=7.20 Hz, 3H), 2.17 (s, 3H), 3.16 (m, 2H), 6.68 (br s, 1H), 7.00 (s, 1H), 7.47 (s, 1H), 9.33 (s, 1H), and 10.43 (br s, 1H), MS: 252.18 (M+H+).
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CSc1ccc(N)cc1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Product: CSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a yellow powder (yield 95%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH:6]=[O:7])=[C:8]([O:10][CH3:11])[CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(OCc2ccccc2)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
To a solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.0 g, 5.49 mmol), benzyl alcohol (0.65 g, 6.01 mmol) and tributylphosphine (1.5 g, 7.41 mmol) in tetrahydrofuran (120 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.8 g, 7.13 mmol) by small portions, and the mixture was stirred at room temperature for 18 hrs. Diethyl ether (120 ml) was added to the reaction mixture, the precipitated insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-1:1) to give 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) as pale-yellow crystals. Separately, a solution of ethyl diethylphosphono acetate (1.1 g, 4.91 mmol) and 60% sodium hydride (0.17 g, 4.25 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. A solution of 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) was added, and the mixture was stirred while elevating the temperature to room temperature for 5 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether-hexane to give the title compound (1.2 g) as colorless crystals. yield 64%. MS 343.1 (MH+).
Reaction SMILES: Br.[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([N:12](C)C)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[NH2:16]N>C(O)CO>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][NH2:16])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: Cc1cccc2sc(N(C)C)nc12
Agent: Br
Solvent: O
Solvent: OCCO
Product: Cc1cccc2sc(NN)nc12
Temperature: 140 °C
Yield: 79 %

Procedure:
4-Methyl-2-dimethylaminobenzothiazole hydrobromide (10.95 g.; 0.04 mole), 85% hydrazine hydrate representing 8.01 g., 0.12 mole, and 33 ml. of ethylene glycol were mixed at room temperature and the mixture heated to 140°C. under nitrogen atmosphere. The reaction mixture was maintained at this temperature overnight. After 39 hours of reaction time, the reaction was cooled, diluted with 33 ml. of water, and filtered to separate the desired 4-methyl-2-hydrazinobenzothiazole compound. It was washed with water and dried 2 hours at 65°C. in vacuo, 5.43 g., 79% yield. The product was subjected to nmr, which showed about 5-10% of starting material. The melting point was 161°-166°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][C:9](=O)[CH2:8][CH2:7][C:6]=2[CH:13]=1.CSC.B>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Agent: B
Solvent: CSC
Solvent: COCCOC
Product: Brc1ccc2c(c1)CCCNC2
Yield: 13.9 %

Procedure:
To a solution of 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (35 g, 146 mmol) in 1,2-dimethoxyethane (400 mL) was added a solution of borane dimethyl sulfide complex (1.0 M in tetrahydrofuran, 40 mL) under nitrogen and the resulting mixture was stirred under reflux overnight. The reaction was quenched with methanol, acidified with 2 M hydrochloric acid and then stirred for further 2 hours. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 4.6 g of product. MS obsd. (ESI+) [(M+H)+] 226. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (d, J=5 Hz, 1 H), 7.15-7.13 (dd, J=2.0, 8.0 Hz, 1 H), 6.89 (d, J=8 Hz, 1 H), 3.79 (s, 2 H), 3.11-3.08 (m, 2 H), 2.82-2.79 (m, 2 H), 2.38 (brs, 1 H), 1.63-1.61 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>CCOCC.CCOC(C)=O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:15]1[CH:16]=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1)(=[O:4])=[O:5]
Reactant: Clc1ncccn1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)n1ccnc1-c1ccnc(Cl)n1
Reaction time: 1 h
Yield: 4.5 %

Procedure:
N-BuLi [2.5M in hexane] (4 ml, 10 mmol) added at −78° C. to a solution of N,N-dimethyl imidazole-1-sulphonamide (1.75 g, 10 mmol) in dry ether (60 ml), stirred 1 hour, anion transferred to a suspension of 2-chloropyrimidine (1.48 g, 10 mmol) in ether (80 ml) keeping the temperature -30° C., temperature brought to 0° C. and held for 30 min. Reaction quenched with AcOH (0.64 ml) and water (0.1 ml), to the reaction was added THF (2 ml) then DDQ (2.27 g) in THF (10 ml) and stirred 0/N. Reaction diluted with EtOAc, solid filtered off and filtrate washed with water (3×) then ice cold 0.5% NaOH, organic layer dried over MgSO4, filtered and concentrated under reduced pressure, residue was purified by column chromatography to give the product (130 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:36]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:2]([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:48](=[O:49])[CH2:47][NH:46][C:44]([O:43][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:45])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
L-Alanyl-L-prolyl-L-proline benzylester hydrochloride (2.46 g, 6 m mole) was dissolved in dimethylformamide (10 ml) and triethyl amine (0.48 ml, 6 m mole) was added thereto while cooling to neutralize the solution, and then benzyloxycarbonylglycine N-hydroxysuccinimideester (2.02 g, 6.6 m mole) was added thereto. The reaction solution was stirred for 2 days while it had been adjusted to pH around 7 with triethyl amine, and ethyl acetate (150 ml) was added thereto and the solution was washed with 1N hydrochloric acid, 5% aqueous sodium bicarbonate and water in order. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a residue. The thus obtained residue was recrystallized with ethyl acetate to give N-benzyloxycarbonyl glycyl-L-alanyl-L-prolyl-L-proline benzylester (1.3 g). The product as produced above (1.2 g) was dissolved in methanol (50 ml) and then, hydrogen gas was passed through the solution in the presence of palladium-carbon as a catalyst for 3 hours. The catalyst was separated by filtration and the solvent was distilled off. The thus obtained residue was recrystallized with methanol-ether to give glycyl-L-alanyl-L-prolyl-L-proline (688 mg).
Reaction SMILES: [CH3:1][S:2]([O-])(=O)=O.[NH2:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:16]1[CH:20]2[O:21][CH2:22]C(O)[CH:19]2[O:18][CH2:17]1>>[NH2:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[CH:20]2[O:21][CH2:22][C@H:1]([SH:2])[CH:19]2[O:18][CH2:17]1
Reactant: Nc1ncnc2c1ncn2C1COC2C(O)COC21
Reactant: CS(=O)(=O)[O-]
Product: Nc1ncnc2c1ncn2[C@@H]1COC2C1OC[C@@H]2S

Procedure:
In an analogous manner to Example 3 the title compound is prepared from the methanesulfonate derivative of 6-(6-amino-purin-9-yl)-hexahydro-furo[3,2-b]furan-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH:10]=[CH:11][CH2:12][C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:13]([CH2:12]/[CH:11]=[CH:10]/[C:9](=[O:16])[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[O:15])=[CH:27][CH:26]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)CC=CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)C/C=C/C(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 4-(3,4-dichlorophenyl)-4-oxo-2-butencarboxylic acid (2.0 g, 8.16 mmol) and oxalyl chloride (0.84 ml, 9.79 mmol) in chloroform (25 ml), was maintained at room temperature under nitrogen atmosphere for 3 hours. The solvent was removed under vacuum and the residue evaporated twice from toluene with the rotary evaporator to remove traces of oxalyl chloride. The thus obtained acid chloride was dissolved in methylene chloride (15 ml) and cooled at -78° C., under inert atmosphere. TEA (1.25 ml, 9.79 mmol), 4-DMAP (0.1 g, 0.816 mmol) and 4-methoxy benzylamine (1.12 g, 8.16 mmol) were added while magnetic stirring was continued at -78° C. for 4 hours. The reaction mixture was allowed to warm at room temperature and then diluted with methylene chloride (100 ml); the organic phase was washed with 1N HCl (3×10 ml), saturated potassium bicarbonate (3×10 ml), brine (3×15 ml), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography, using cyclohexane/ethyl acetate 0÷5 as eluent. The title compound was obtained as a light yellow solid (1.84 g, 62w) (m.p. 169°-170° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)[CH:8]=2)[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O.[O-]S([O-])(=O)=O.[Mg+2]>CN(C)C(=O)C.C(Cl)Cl.C(OC(=O)C)C.CCCCCC>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:22][CH:21]=1)[CH:8]=2)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3ccc(F)cc3)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: CCn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 140 °C
Reaction time: 15 h
Yield: 21.5 %

Procedure:
To 1-[9-Ethyl-6-(4-fluoro-benzoyl)-9H-carbazol-3-yl]-ethanone (1.30 g; 25.6 mmol) in N,N-Dimethylacetamide (DMA) (10 ml) is added morpholine (1.07 g; 12.3 mmol) at 100° C. This reaction mixture is stirred at 140° C. for 15 h. After the reaction is completed, the reaction mixture is poured into H2O, then, a beige solid was obtained by filtration. The solid is dissolved in CH2Cl2, followed by dying over anhydrous MgSO4. Condensation under reduced pressure affords a beige solid as crude product. (1.13 g) The pure product was obtained by silica gel column chromatography with ethylacetate/hexane (1/3-1/1) as eluent. (1.03 g, 67%). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 1.50 (t, 3H), 2.72 (s, 3H), 3.36 (t, 4H), 3.89 (t, 4H), 4.44 (q, 2H), 6.96 (d, 2H), 7.48 (dd, 2H), 7.86 (dd, 2H), 8.05 (dd, 1H), 8.16 (dd, 1H), 8.58 (d, 1H), 8.73 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:13][CH3:14].[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[NH2:15][C:16]1[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([N:13]([CH2:12][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([C:4]=2[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:14])=[O:26])=[CH:18][CH:17]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c(C)c2ccccc2n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a stirred solution of 1,3-dimethyl-2-(methylaminomethyl)-1H-indole (0.6 g, 3.2 mmole) in 1:1 DMF/CH2Cl2 (25 mL) was added (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.50 g, 3 mmole), HOBt.H2O (0.43 g, 3.2 mmole), and DCC (0.66 g, 3.2 mmole). After stirring at RT for 16 hr the reaction was concentrated under vacuum. Purification by flash chromatography on silica gel (3% methanol/CHCl3) gave the title compound (0.83 g, 83%) as an off-white solid: LCMS (ES) m/e 335.4 (M+H)+.