Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=O)[O:22]C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([CH:3]2[C:2](=[O:1])[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]2=3)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1cccc(Cl)c1)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 18.2 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 60 ml of hexamethylphosphoric acid triamide is added dropwise to a suspension of 5.9 g of a 50% strength sodium hydride/mineral oil suspension in 180 ml of hexamethylphosphoric acid triamide whilst cooling, the reaction temperature being kept below 15°. After stirring for one hour at room temperature, 30.4 g of phenyl N-(3-chlorophenyl)-carbamate are added in portions, with external cooling. The mixture is stirred for a further 16 hours at room temperature and poured onto a mixture of 100 ml of 2 N hydrochloric acid and 1,000 g of ice, whereupon an oil separates out; this oil crystallises on leaving to stand for several hours. The crystals are collected and dissolved in 300 ml of diethyl ether. The solution is washed with water and the organic phase is separated off, dried over sodium sulphate and evaporated to dryness. The residue is recrystallised from ether and gives N-(3-chlorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide with a melting point of 175°-177°.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:8][C@@H:7]([NH2:9])[C@H:6]([NH2:10])[CH2:5]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29])=[CH:22]2>CN(C)C=O>[CH3:2][O:3][CH:4]1[CH2:8][C@@H:7]([NH:9][C:28]([C:23]2[NH:24][C:25]3[C:21]([CH:22]=2)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=3)=[O:29])[C@H:6]([NH2:10])[CH2:5]1
Reactant: COC1C[C@@H](N)[C@H](N)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1C[C@@H](N)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.3 %

Procedure:
(1R*,2R*)-4-Methoxy-1,2-cyclopentanediamine hydrochloride (470 mg) was suspended in N,N-dimethylformamide (5 ml), and triethylamine (0.966 ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (805 mg) were added to stir the mixture at room temperature for 4 days. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane were added to the residue to conduct liquid separation. The resultant organic layers was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:9) to obtain (1R*,2R*)-4-methoxy-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine (mixture of stereoisomers at 4-position) (268 mg) as yellow powder.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:15][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:7][C:5]=2[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: NS(=O)(=O)c1ccc2oc(S)nc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2cc(S(N)(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of 2-mercapto-benzooxazole-5-sulfonic acid amide (17.0 g, 73.8 mmol, 1.0 equiv) in anhydrous DMF (200 mL) was added anhydrous K2CO3 (51.0 g, 369.1 mmol, 5.0 equiv) and methyl iodide (16.1 mL, 36.7 g, 258.4 mmol, 3.5 equiv). After stirring for 3 h at rt, the K2CO3 was removed by filtration and the reaction mixture concentrated by evaporation under reduced pressure. The residue was washed with ethyl acetate (50 mL) give 17.4 g (97%) of the title compound. 1H NMR (300 MHz, DMSO): δ 2.80 (s, 3H), 7.47 (br s, 2H), 7.83 (s, 2H), 8.07 (s, 1H). 13C NMR (75 MHz, DMSO): δ 4.28, 110.47, 115.71, 122.04, 140.99, 141.37, 152.92, 167.84. MS (ISP): 244.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][N:17]([C:22](=[O:44])[CH2:23][C@H:24]([NH:36]C(=O)OC(C)(C)C)[CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:16]1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[NH2:36][C@H:24]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[CH2:23][C:22]([N:17]1[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([C:7]2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:16]1)=[O:44].[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: COCCCn1c(C2CC(C)CN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c(C2CC(C)CN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The residue 136H was dissolved in 25% trifluoroacetic acid and stirred at room temperature for 3 hr. Solvent was removed under vacuum and purified by preparatory LC/MS (25-35% CH3CN in H2O) to give (3R)-3-amino-1-(3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)-5-methylpiperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (246) as a TFA salt (13 mg, 9%). ESI-MS:m/z 499.5 (M+H)+.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.CCN(C(C)C)C(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1OB(O)c2cc(OS(C)(=O)=O)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2 mmol), DIPEA (774 mg, 6 mmol) in DCM (10 mL) was slowly added MsCl (366 mg, 3.2 mmol) at −78° C. The reaction mixture was stirred overnight at room temperature, quenched with saturated NH4Cl and washed with saturated NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in next step reaction without further purification. MS (ESI) m/z=329 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[C:14]([NH2:20])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][C:25]2[C:26]3[S:33][CH:32]=[C:31]([C:34](O)=[O:35])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH:20][C:34]([C:31]4[C:27]5[N:28]=[CH:29][N:30]=[C:25]([NH:24][CH:21]6[CH2:22][CH2:23]6)[C:26]=5[S:33][CH:32]=4)=[O:35])[C:15]([CH3:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1N
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1NC(=O)c1csc2c(NC3CC3)ncnc12
Yield: 38.5 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated, except for using N1-(4-chlorophenyl)-6-methylisoquinolin-1,5-diamine (0.04 g, 0.14 mmol) and 4-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.18 mmol) obtained in <Step 2> of Example 1 to obtain the title compound (27 mg, 38%).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:17][C:15]1[N:16]=[C:11]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1cnn(C2CC2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(Br)nc(Nc2cnn(C3CC3)c2)c1=O
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 109b (378 mg, 3.07 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (906 mg, 3.38 mmol), cesium carbonate (3.00 g, 9.21 mmol), and 1,4-dioxane (45 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (151 mg, 0.261 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (141 mg, 0.154 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×45 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 28% yield (266 mg) of 109c as an off-white solid: mp 228-230° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.21 (s, 1H), 3.70 (m, 1H), 3.41 (s, 3H), 0.96 (m, 4H); MS (ESI+) m/z 310.0 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1.CCOCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extractd 2 x with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][NH:20][C:16]=2[N:17]=[CH:18][N:19]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([Cl:13])[C:15]=3[CH:22]=[CH:21]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
Diethyl azodicarboxylate (14.4 g, 82.7 mmol) was added dropwise over a period of 1 h (exothermic) to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (6.4 g, 41.4 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (25.0 g, 124 mmol), and triphenyl phosphine 21.7 g, 82.7 mmol) in THF (500 mL). The reaction mixture was stirred at room temperature 3 h and concentrated in vacuo. The crude reaction mixture was washed with EtOAc, filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 5:95→15:85 EtOAc:hexanes) provided the title compound as a white solid (6.5 g, 93%). MS: 338 (MH+); HPLC Rf: 6.21 min. (HPLC method 4); HPLC purity: 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[I:11]Cl>C(Cl)Cl>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10]
Reactant: ClI
Reactant: N#Cc1ccc(N)c(Cl)c1
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(N)c(I)c1
Reaction time: 12 h
Yield: 35.5 %

Procedure:
4-Amino-3-chloro-benzonitrile (100 mg, 0.66 mmol) and ICl (1.1 eq, 0.72 mmol, 117.05 mg) were added in methylene chloride. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to similar procedure to step 2 of Example 8 to obtain 4-Amino-3-chloro-5-iodobenzonitrile (65.2 mg, 35.80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]([C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:24]#[N:25])[CH:27]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: N#Cc1cccc(O)c1
Product: COc1ccc(-c2cc(Oc3cccc(C#N)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (175 mg, 0.536 mmol) and 3-cyanophenol were reacted as starting materials at 150° C. for 19 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (165 mg, 75.2%). Melting point: 169.9-172.7° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC/C=C/CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC/C=C\CCOS(=O)(=O)c1ccc(C)cc1
Yield: 99 %

Procedure:
This compound was synthesized as a colorless oil from (E)-hex-3-en-1-ol (70.0 mg, 0.70 mmol), TsCl (173.5 mg, 0.91 mmol), Et3N (109.2 mg, 1.05 mmol), and DMAP (85.5 mg, 0.70 mmol) in 99% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.78 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 5.58-5.35 (m, 1H), 5.28-5.08 (m, 1H), 3.99 (t, J=7.0 Hz, 2H), 2.44 (s, 3H), 2.42-2.31 (m, 2H), 2.07-1.90 (m, 2H), 0.91 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, δH) 144.94, 135.73, 133.33, 130.03, 128.11, 122.27, 70.06, 27.18, 21.86, 20.82, 14.30. ESI-MS: 255.1 (M+H+), 277.1 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[O:18][C@@H:17]([CH2:19][O:20]C(=O)C3C=CC=CC=3)[C@:15](C(=O)C3C=CC=CC=3)([OH:16])[C@:13]2(C(=O)C2C=CC=CC=2)[OH:14])[N:3]=1>CO.N>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:13]2[OH:14])[N:3]=1
Reactant: O=C(OC[C@@H]1O[C@H](n2nc(Br)c3c(=O)[nH]cnc32)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1)c1ccccc1
Agent: N
Solvent: CO
Product: O=c1[nH]cnc2c1c(Br)nn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 93.8 %

Procedure:
3-Bromo-1-(2′,3′,5′-O-tribenzoy-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 24 (280 mg, 0.43 mmole) was dissolved in MeOH saturated with NH3 at 0 C (25 mL). The solution in a sealed, stainless steel bomb was heated at 100 C for 6 h. After cooling, ammonia and methanol were evaporated. The residue was dissolved in water (40 mL), washed with EtOAc (4×20 mL), and concentrated. The residue was soaked in acetonitrile and the resulting solid filtered, dried under vacuum to give 3-Bromo-1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 25 as a white solid (140 mg, 95%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](O)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([Cl:27])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
3.55 g (10.5 mmol) of 1-acetyl-3-[1-hydroxy-1-(4-methyl-phenyl)methylidene}-5-nitro-2-indolinone and 2.40 g (11.5 mmol) of PCl5 are heated in 60 ml toluene for 2 hours at 80° C. The mixture is evaporated down in vacuo, fresh toluene is added to the evaporation residue, it is evaporated down again and this procedure is repeated once more. The evaporation residue is dissolved in a little toluene with heating. During slow cooling an isomer, probably the (Z) isomer, crystallised out. A mixture of the (Z) and (E) isomers was also obtained from the mother liquor by column chromatography on silica gel with CH2Cl2.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[F:17][C:18]([F:34])([F:33])[C:19]1[CH:32]=[CH:31][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:21][CH:20]=1>>[F:17][C:18]([F:33])([F:34])[C:19]1[CH:32]=[CH:31][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:21][CH:20]=1
Reactant: NCCCCCCOc1ccc(C(F)(F)F)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCCCCCOc2ccc(C(F)(F)F)cc2)c(Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-(4-trifluoromethylphenoxy)-hexylamine. The reaction mixture was heated to reflux for 4 hours instead of stirring 18 h at r.t.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(=O)([O-])O.[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CCC(CC(=O)c2ccc(N3CCCCC3)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture consisting of 1.84 g of 1-acetyl-4-(4-fluorobenzoylmethyl)piperidine and 5 ml of piperidine was stirred under heating at 100° C. for 20 hours. After completion of the reaction, the reaction mixture was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. After drying, the solvent was ditilled off and the oily residue was purified by silica gel column chromatography (eluent: ehtyl acetate) to give 2.2 g of a pale yellow oil.
Reaction SMILES: CC[O:3]C(C)=O.[F:7][C:8]([F:40])([C:29]1([OH:39])[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]([CH3:38])([CH3:37])[CH2:30]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:18][N:17]=1)=[O:10].[ClH:41]>CCCCC>[OH2:3].[ClH:41].[F:40][C:8]([F:7])([C:29]1([OH:39])[CH2:30][C:31]([CH3:38])([CH3:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH2:34]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:18][N:17]=1)=[O:10]
Reactant: CCOC(C)=O
Agent: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COc3cccnc3)on2)C1
Agent: Cl
Solvent: CCCCC
Product: O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an AcOEt (50 ml) solution of Compound 40 (2.24 g) obtained in Example 2, HCl (50 ml, 4.0 N in AcOEt) was added and the mixture was stirred at room temperature for 15 hours, and after adding pentane (140 ml), the mixture was stirred for 8 days. The residue obtained by concentrating the reaction mixture was recrystallized (MeOH/Et2O) to give the titled compound (2.23 g, colorless powder.)
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16]C(=O)OC(C)(C)C)[CH:14]=3)[NH:9][CH:8]=2)=[CH:3]1>CO>[O:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH2:16])[CH:14]=3)[NH:9][CH:8]=2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Agent: Cl
Solvent: CO
Product: Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
4.0 M aqueous HCl (0.83 mL, 3.32 mmol) was added to a suspension of 47 (90 mg, 0.30 mmol) in MeOH (0.17 mL) and the mixture was stirred at r.t. overnight. Concentrated aqueous HCl (0.2 mL, 2.2 mmol) was added and stirring continued for 5 h. The mixture was concentrated to dryness in vacuum and separated by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 48 (41.64 mg, 70%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 6.61 (dd, J=1.8, 0.8 Hz, 1H), 7.32 (s, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.45 (dd, J=3.3, 1.7 Hz, 1H), 7.68 (dd, J=2.3, 1.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H); MS (ES) m/z 241 (MH++MeCN).
Reaction SMILES: CN1CCOCC1.[NH:8]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].O.[NH2:32][C@H:33]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH:34]([CH3:36])[CH3:35].S(O)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[NH:8]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:9]([C:18]([NH:32][C@H:33]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:20])[CH2:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
15.83 g of 1-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate and 9 ml of N-methylmorpholine were added to a solution of 13.65 g of Z-Asp(OBut)-OH.H2O and 15.9 g of Val-OBzl.TosOH in 250 ml of DMF. After stirring for 2 hours the reaction mixture was evaporated in a vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution, dried over Na2SO4, filtered and evaporated. The residue was crystallized from diethyl ether/hexane and there were obtained 17.5 g of Z-Asp(OBut)-Val-OBzl of m.p. 99°; [a]D20 -27.7° (c=1, MeOH).