Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH:22]3[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2o1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
The above prepared 5-hydroxy-benzofuran-2-carboxylic acid ethyl ester (1.50 g, 7.27 mmol) was dissolved in 36 mL of THF and treated successively at 10° C. with 1-isopropyl-piperidin-4-ol (1.46 g, 1.4 eq.), triphenylphosphine (2.67 g, 1.4 eq.) and DIAD (2.00 mL, 1.4 eq.), and the mixture then kept at ambient temperature for another 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98), yielded finally 1.36 g of the title compound as light yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[OH:9][C:10]1[CH2:15][CH:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([Br:24])[C:17]=2[CH3:25])[CH2:13][C:12](=[O:26])[C:11]=1[C:27](=O)[CH2:28][CH3:29].C(O)C>O>[CH2:2]([O:5][N:6]=[C:27]([C:11]1[C:12](=[O:26])[CH2:13][CH:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([Br:24])[C:17]=2[CH3:25])[CH2:15][C:10]=1[OH:9])[CH2:28][CH3:29])[CH:3]=[CH2:4]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(Br)c2C)CC1=O
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(Br)c2C)CC1=O
Yield: 57.3 %

Procedure:
Allyloxyamine hydrochloride (0.17 g) and then a solution of sodium hydroxide (0.06 g) in water (1 ml) were added to a stirred mixture of 3-hydroxy-2-propionyl-5-(3-bromo-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.50 g, 1.37 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation under reduced pressure and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(allyloxyimino)propyl]-3-hydroxy-5-(3-bromo-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.33 g, 57.4%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@H:36]1[CH2:41][C:40]2[C:42]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][CH2:37]1>CN(C)C=O>[CH3:52][N:49]1[CH2:50][CH2:51][N:46]([C:42]2[C:40]3[CH2:41][C@H:36]([NH:35][C:18](=[O:19])[C:17]4[CH:21]=[CH:22][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH2:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[CH2:37][O:38][C:39]=3[CH:45]=[CH:44][CH:43]=2)[CH2:47][CH2:48]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(Cc5ccccc5)CC4)cc2)CO3)CC1
Temperature: 75 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
A suspension of 4-(4-benzylpiperazin-1-yl)benzoic acid (1.3 g, 4.2 mmol) and 1,1′-carbonyldiimidazole (740 mg, 4.2 mmol) in N,N-dimethylformamide (30 mL) was heated to 75° C. for 1.5 h. The reaction mixture was cooled to 50° C. and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran (1.0 g, 4.0 mmol) was added. The solution was stirred at 50° C. for 20 h and the solvent was evaporated in vacuo giving 3.5 g of a crude product. Purification by chromatography on a silica gel column using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent gave 1.7 g (80% yield) of the title compound as a pale yellow solid: mp sinters>85° C.; TSPMS m/z (relative intensity) 526 (100, M+1); [α]22D−130° (c 1.0, chloroform).
Reaction SMILES: [H-].[Li+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:6].I[CH2:15][CH:16]([CH3:18])[CH3:17].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9](=[O:13])[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc[nH]c(=O)c1
Reactant: CC(C)CI
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(CC(C)C)c(=O)c1
Reaction time: 0.17 h

Procedure:
LiH (78 mg) was suspended in DMF (5 ml), and a suspension of methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (500 mg) in DMF (5 ml) was added dropwise thereto at room temperature. The suspension was stirred as it was, and a solution of 1-iodo-2-methylpropane (506 μl) in DMF (5 ml) was added dropwise thereto over 10 min, followed by stirring at 50° C. for 15 hours. To the reaction solution was added 1M HCl at 0° C., followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over anhydrous MgSO4, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:EtOAc=90:10 to 50:50) to obtain methyl-1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (440 mg) as white powders.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([Mg]Cl)[CH:14]=[CH2:15].O>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]([OH:12])[CH2:11][CH2:15][CH:14]=[CH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Cl
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
To a stirred solution of benzyl-(S)-glycidyl ether (5.0 g, 30.5 mmol) in THF (100 ml) was added allylmagnesium chloride (1.0 M in Et2O, 30.5 ml, 30.5 mmol) at −78° C., and the resulting mixture was gradually warmed up to rt with stirring. The mixture was poured into water and concentrated in vacuo, then extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyloxy-2-(R)-hydroxy-5-hexene (2.18 g, 35%) as a colorless oil: 1H-NMR (CDCl3) δ1.52-1.60 (m, 2 H), 2.11-2.25 (m, 2 H), 2.34 (d, J=3.2 Hz, 1 H), 3.35 (dd, J=9.6, 8.0 Hz, 1 H), 3.52 (dd, J=9.6, 3.2 Hz, 1 H), 3.84-3.86 (m, 1 H), 4.57 (s, 2 H), 4.96-5.07 (series of m, 2 H), 5.78-5.88 (m, 1 H), 7.29-7.38 (m, 5 H); MS (ESI) m/z, 224 (M++NH4+).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH:46]([CH3:48])[CH3:47])[CH3:45])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)N(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C(C)C)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 35.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-isopropyl-N-methylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.7 mg) was obtained.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:34]([NH:33][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=2[Cl:25])=[O:35])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 33.6 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (62 mg, 0.18 mmol) and 2,3-dichlorophenylisocyanate (41 mg, 0.22 mmol) were coupled to form the desired urea (32 mg, 34%). LC-MS (m/z) 528.0 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[NH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[CH2:3]1.[H-].[Na+].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[N:8]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:7]=[CH:6][C:5]=2[C:4](=[O:11])[CH2:3]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC1(C)CC(=O)c2cc[nH]c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c1CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A solution of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-4-one (3.8 g, 23 mmol) in DMF (25 mL) was cooled to 0° C. and NaH (1.02 g of a 60% dispersion in mineral oil, 26 mmol) was added portionwise. The mixture was stirred for 30 min then triisopropylsilyl chloride (5.6 mL, 26 mmol) was added at 0° C. and stirring continued for 1 hr. The mixture was warmed to room temperature then extracted with ether (3×). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with isohexane: EtOAc (9:1), to give the title compound (2.9 g, 39%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.11 (6H,s), 1.14 (18H,d, J 7.5 Hz) 1.51 (3H,heptet, J=7.5 Hz), 2.34 (2H,s), 2.71 (2H,s), 6.64 (1H,d, J=3.1 Hz), 6.71 (1H,d, J=3.1 Hz). MS (ES+) 320 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37].CCOC(C)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[N:12]=2)[CH:7]=1
Reactant: CC(C)=CCBr
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nn(CC=C(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a suspension of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (114.0 mg, 0.31 mmol) and cesium carbonate (201.4 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL), was added 4-bromo-2-methyl-2-butene (53 μL, 0.46 mmol). The reaction mixture was stirred for 3 hours at room temperature, then EtOAc was added. The organic layer was washed 1× each with water and saturated brine solution. The organic layer was separated, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (20-100% EtOAc:Hex) to afford N-(3-(5-chloro-2-methoxyphenyl)-1-(3-methylbut-2-enyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow foam (67 mg, 0.15 mmol). Acetone and water (1 mL each) were then added, followed by osmium tetraoxide (1.89 mg, 0.0074 mmol), and N-methylmorpholine-N-oxide in water (1:1, N-methylmorpholine-N-oxide:Water, 37 mg). The reaction mixture was stirred for 3 hours at room temperature. Celite was added and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (50-100% EtOAc*:Hex, *EtOAc also contained 10% MeOH), and then by chiral SFC to separate enantiomers to give 11.2 mg and 15.8 mg of the title compounds as white solids. LCMS (ESI) m+H=471.1; 1H NMR (500 MHz, DMSO) δ 9.69 (s, 1H), 9.34 (d, J=6.9, 1H), 8.78 (d, J=4.0, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 7.49 (dd, J=8.8, 2.6, 1H), 7.42 (d, J=2.6, 1H), 7.29 (dd, J=10.0, 4.6, 2H), 5.05 (d, J=6.3, 1H), 4.53 (s, 1H), 4.43 (d, J=13.5, 1H), 3.95 (dd, J=13.5, 10.1, 1H), 3.85 (s, 3H), 3.60 (s, 1H), 1.16 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][O:5][CH2:6][CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1.O>[CH2:6]([O:5][CH2:4][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][NH:1][C:23](=[O:24])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOCC(CN)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (1-amino-3-ethoxypropan-2-yl)carbamate (0.45 g, 2.6 mol) and sodium carbonate (0.29 g, 3.2 mol) in THF (5 mL) and water (3 mL) was added dropwise benzyl chloroformate (0.58 g, 3.4 mol) at 0° C. and then the reaction mixture was allowed to warm to ambient temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to give benzyl tert-butyl (3-ethoxypropane-1,2-diyl)biscarbamate. MS ESI calc'd. for C18H29N2O5 [M+H]+ 353. found 353. 1H NMR (400 MHz, CD3OD) δ 7.36-7.35 (m, 5H), 5.09 (s, 2H), 3.52-3.49 (m, 1H), 3.42-3.32 (m, 6H), 1.45 (s, 9H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[S:17]2(=[O:34])=[O:33])=[CH:11][CH:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[S:17](=[O:33])(=[O:34])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[C:19](=[O:21])[CH2:20]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CN)cc3)S2(=O)=O)c(OC)c1
Reaction time: 0.5 h

Procedure:
The title A compound, {4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzyl}-carbamic acid t-butyl ester (400 mg, 0.79 mmol) is dissolved in EtOAc (20 mL) with gentle warming. The cooled solution is saturated with HCl gas and stirred for 30 min. The resulting precipitate is collected by filtration, washed with EtOAc and dried to give 5-(4-aminomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one hydrochloride: [M+1]+=406.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C:29]1([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C:29]1([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)C1(N)CCCC1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NC2(C(=O)N(C)C)CCCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.81 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 76-3 (2.89 mmol, crude form) as starting materials, 0.27 g of the title compound (pale yellow solid) was obtained by a similar method to Step 4-2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][OH:16])[CH2:9]1)C1C=CC=CC=1.[ClH:17].O1CCOCC1>CO.[OH-].[OH-].[Pd+2]>[ClH:17].[OH:16][CH2:15][CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: OCC1CNCCC1O
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 1 g (4.52 mmol) (rac)-1-benzyl-3-hydroxymethyl-piperidin-4-ol (ca 1:1 diast mixture, Synthesis (1999), 11, 1937-1943) in 25 ml of MeOH was treated with a solution of HCl in dioxane (1.24 ml, 4 M in dioxane, 4.97 mmol) and 95 mg of Pd(OH)2/C (20%) and was stirred over H2-atmosphere for 16 h. After filtration, new catalyst was added (95 mg of Pd(OH)2/C (20%)) and stirred over H2-atmosphere for 2 days. After filtration, the solution was evaporated under reduced pressure to yield 0.66 g (86%) of the title compound as a ca 1:1 cis/trans mixture, MS: 132.3 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][CH3:12])=[N:7][N:8]=1.[CH2:13]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:13]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][CH3:12])=[N:7][N:8]=2)=[O:29])=[CH:31][CH:32]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CCCSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1nnc(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-propylthio-1,3,4-thiadiazole (1.2 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.9 g) and carbonyldiimidazole (1.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.3 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([Cl:19])[N:5]=[CH:4][CH:3]=1.[CH:20](=O)[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C(#N)C.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:19][C:6]1[C:7]2[C:8](=[O:9])[N:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[NH:1][C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccccc1C1Nc2ccnc(Cl)c2C(=O)N1CCc1ccccc1
Temperature: 20 °C
Yield: 93.6 %

Procedure:
To a solution of 4-amino-2-chloro-N-phenethyl-nicotinamide (808 mg, 2.93 mmol) in 8 mL of acetonitrile at 20° C. was added 0-anisaldehyde (399 mg, 2.93 mmol) and a catalytic amount of p-toluenesulfonic acid (10 mg, 0.059 mmol). The resulting solution was then heated to reflux under Dean-Stark trap for 12 hours. The reaction mixture was cooled to 20° C. and diluted with ethyl acetate. The mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed 3× with NaHCO3, 1× with water, 1× with brine and then dried over anhydrous Na2SO4, filtered and evaporated to dryness. 1.08 g of pale yellow sticky solid was obtained. The resulting crude material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Clc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.022 g, 0.06 mmol) and EtOH (2.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.015 g, 0.08 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.24 ml, 0.24 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.008 g, 27%); 1H-NMR (500 MHz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2pyridyl), 3.72 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.13 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.40 (d, J=5.8 Hz, 2H, pyridine 3-H, 5-H), 7.49 (d, J=1.5 Hz, 1H, pyrazole-H), 7.86 (d, J=1.8 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.45 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]([O:28]C)=[O:27])[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].C(O)(=O)C>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([C:26]([OH:28])=[O:27])[CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 60 °C
Yield: 63.4 %

Procedure:
A mixture of methyl 3-chloro-4-[(2,4-difluorobenzyl)oxy]-5′,6-dimethyl-2-oxo-2H-1,4′-bipyridine-2′-carboxylate (0.13 g, 0.3 mmol) and 1.5 N NaOH (0.25 mL, 0.375 mmol) in dioxane (0.25 mL) was heated at 60° C. for 1 h and stirred at room temperature for an additional hr. The reaction mixture was acidified with acetic acid, and extracted with ethyl acetate (2×15 mL). The combined organic extract were washed with water and concentrated under reduced pressure to give the title compound as a white powder (0.08 g) which was used without purification in the next step. ES-MS, m/z=421 (M+H).