Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH:9]1([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Fc1ccc(S)cc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ccc(SC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
A suspension of 4-fluorobenzenethiol (80 g, 0.625 mol), cyclobutylbromide (45 g, 0.33 mol) and Cs2CO3 (108 g, 0.33 mol) in DMSO (1.5 L) was heated to 70° C. and stirred overnight. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was filtered to remove inorganic salts, and the filtrate was partitioned between diethyl ether (1.5 L) and water (1 L). The aqueous layer was extracted with diethyl ether (700 mL×3). The combined organic phases were washed sequentially with water (1 L×2), then brine (1 L), dried over MgSO4 and concentrated in vacuum to give cyclobutyl(4-fluorophenyl)sulfane (64.8 g, 84.8%) as a pale yellow oil. Cyclobutyl(4-fluorophenyl)sulfane (61.8 g, 0.34 mol) was dissolved in CH2Cl2 (2 L) and cooled to −15° C., m-CPBA (150.4 g, 0.742 mol) was added portion wise while keeping the temperature between −15° C. and −10° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 3-4 h. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. The reaction mixture was partitioned between CH2Cl2 (2 L) and water (1 L). The organic layer was washed with saturated NaHCO3 solution (1 L) and brine (1 L), dried over MgSO4, filtrated and concentrated in vacuum to give the title compound (59 g, 81.1%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)=[C:7]([F:35])[CH:6]=1)=[O:4].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:37][OH:38])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:13][CH:12]=2)=[C:7]([F:35])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)c(F)c1

Procedure:
In analogy to example 74, step 7, from 2-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.8:1) as a white foam, MS (ESI+): m/z=483.2073 ([M+H]+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1([NH:11][CH:12]2[C:21]3[C:16](=[C:17]([CH2:22][OH:23])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:24][CH3:25])[CH2:14][CH2:13]2)[CH2:10][CH2:9]1.[OH-].[Na+]>C(O)=O>[CH:1]([N:11]([CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][OH:23])[CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:24][CH3:25])[CH2:14][CH2:13]1)[CH:8]1[CH2:9][CH2:10]1)=[O:3]
Reactant: CCN1CCC(NC2CC2)c2cccc(CO)c21
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCN1CCC(N(C=O)C2CC2)c2cccc(CO)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (0.5 ml) and formic acid (0.25 ml) were stirred for 1 hour at 60° C, and to this mixture 4-cyclopropylamino-8-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.37 g) was added under ice-cooling and the mixture was stirred overnight at room temperature The reaction mixture was adjusted to alkalinic with 30% aqueous solution of sodium hydroxide under ice-cooling, stirred for 0.5 hour, sequentially extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate The residue, obtained by distilling off the solvent, was purified by silica gel column chromatography [eluent: dichloromethane-methanol (75:1)]to give 4-(N-formyl-N-cyclopropylamino)-8-hydroxymethyl1-ethyl-1,2,3,4-tetrahydroquinoline (0.35 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: COc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 75 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-methoxybenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (20) (I, Ar=2-methoxyphenyl) in a 75% yield, mp 216° C. 1H NMR δ [(CD3)2SO] 11.70 (s, 1H), 10.90 (s, 1H), 9.23 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.50 (s, 1H), 7.43 (d. J=8.0 Hz, 1H), 7.43–7.38 (m, 1H), 7.31 (dd, J=8.0, 2.4 Hz, 1H), 7.11–7.01 (m, 3H), 3.68 (s, 3H). Found: C, 69.21; H, 3.80; N, 7.58. C21H14N2O4,1/4H2O requires C, 69.51; H, 4.03; N, 7.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].Cl[CH2:13][C:14](=O)[CH3:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:13]=[C:14]([CH3:15])[N:8]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)CCl
Reactant: COc1cccc(C(N)=O)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc(C)co2)c1
Yield: 64.6 %

Procedure:
To a solution of 3-methoxybenzamide (1.5 g, 9.9 mmol) in toluene (15 mL) was added 1-chloropropan-2-one (1.37 g, 14.9 mmol), and the mixture was stirred at reflux for 16 h. The mixture was cooled and concentrated to give crude product, which was purified via silica gel chromatography eluted with ethyl acetate/petroleum ether (1:5) to give 2-(3-methoxyphenyl)-4-methyloxazole (1.21 g, 64.6% yield) as yellow syrup. LCMS MH+ 190.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][C:18]1[C:19]([Cl:27])=[C:20]([CH:23]=[CH:24][C:25]=1F)[C:21]#[N:22]>CS(C)=O>[Cl:27][C:19]1[C:18]([CH:17]=[CH2:16])=[C:25]([NH:1][CH:2]([CH:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: N#Cc1ccc(F)c(CCBr)c1Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1c(NC(C(=O)O)C(C)O)ccc(C#N)c1Cl
Temperature: 85 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a suspension of D-Threonine (0.299 g, 2.51 mmol) and K2CO3 (1.21 g, 8.72 mmol) in DMSO (24 mL) was added 3-(2-Bromo-ethyl)-2-chloro-4-fluoro-benzonitrile (572 mg, 2.18 mmol) at room temperature. The reaction mixture was heated to 85° C. and stirred for 18 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (20 mL) and extracted with EtOAc (3×60 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×80 mL). The later organic extracts were combined, washed with H2O (3×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a pale yellow solid (594 mg, 97%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.48 (d, J=9 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 6.63 (dd, J=12 and 18 Hz, 1H), 5.97 (d, J=9 Hz, 1H), 5.88 (dd, J=2 and 12 Hz, 1H), 5.78 (dd, J=2 and 18 Hz, 1H), 4.51-4.42 (m, 2H), 4.23-4.21 (m, 1H), and 1.24 (d, J=7 Hz, 3H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3].N1C=CC=CC=1.[NH2:27][C:28]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:29]=1[C:30]([NH:32][C:33]1[CH:37]=[CH:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=2)[N:34]=1)=[O:31]>ClCCl>[Cl:50][C:47]1[CH:48]=[CH:49][C:28]([NH:27][C:2]([C:4]2[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=2)[CH2:7][S:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:3])=[C:29]([C:30](=[O:31])[NH:32][C:33]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([CH3:45])[CH:39]=3)[N:34]=2)[CH:46]=1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3N)n2)cc1C
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Yield: 41.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (185 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (10 mL), and pyridine (140 mg, 1.77 mmol, 3.00 equiv). This was followed by dropwise addition of a solution of 2-amino-5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)benzamide (200 mg, 0.59 mmol, 1.00 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to yield 150 mg (33%) of product as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:30][C:31]([C:33]1[CH:43]=[CH:42][C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1)=[O:32]>CC(C)=O>[O:32]=[C:31]([C:33]1[CH:43]=[CH:42][C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1)[CH2:30][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: c1ccc(CNCC2CCc3ccccc3C2)cc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)CC2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Benzylaminomethyl-1,2,3,4-tetrahydronaphthalene (XXXIV) (2.8 g), N,N-diisopropyl-N-ethylamine (1.44 g) and 4'-(2-bromoacetyl)methanesulfonanilide (Temple, D. L. et al., J. Med. Chem., 19(5), 626-633 (1976)) (3.27 g) were dissolved in acetone (40 ml) and stirred 18 hours at ambient temperature. The solvent was evaporated and the residue was dissolved in CH2Cl2, which was washed with H2O, dried (MgSO4) and evaporated. The HCl salt was made by dissolving the residue in MeOH/concentrated HCl, concentrating, and triturating the residue with 2-PrOH and ether. The solid product, 4'-[1-oxo-2-(N-benzyl-N-((1,2,3,4-tetrahydro-2-naphthyl)methyl)-amino)ethyl]methanesulfonanilide.HCl (XXXIII.HCl), 3 g, had NMR and mass spectra consistent with the structure indicated. It was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[C:9](=[O:10])[N:15]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[C:6]2=[O:8]
Reactant: COc1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
4-Methoxy-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-methoxyphthalic anhydride (1.0 g, 5.6 mmol) {Rao. A. V. R. et al, Indian J. Chem. 1981, 20 (B), 248}, 3-aminopiperidine-2,6-dione hydrogen chloride (0.92 g, 5.6 mmol) and sodium acetate (0.48 g, 6.0 mmol) in acetic acid (20 mL). The product was a white solid (0.44 g, 27% yield); mp, 281.5-282.5° C.; 1H NMR (DMSO-d6) δ2.00-2.08 (m, 1H, CHH), 2.56-2.62 (m, 2H, CH2), 2.82-2.91 (m, 1H, CHH), 3.97 (s, 3H, CH3), 5.08 (dd, J=5.3, 12.8 Hz, 1H, NCH), 7.46 (d, J=7.2 Hz, 1H, Ar), 7.52 (d, J=8.5 Hz, 1H, Ar), 7.84 (d, J=7.8 Hz, 1H, Ar), 11.10 (br s, 1H, NH); 13C NMR (DMSO-d6) δ21.97, 30.92, 48.73, 56.33, 115.24, 116.11, 119.01, 133.19, 137.15, 156.49, 165.37, 166.84, 169.94, 172.79; Anal Calcd for C14H12N2O5: C, 58.33; H, 4.20; N, 9.72. Found: C, 58.23; H, 3.90; N, 9.53.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH:23]=[CH:24][N:25]=[CH:26]5)[CH:19]=[CH:20][C:14]=3[C:13](=[O:31])[NH:12][C:11]=2[CH:32]=1)([CH3:6])[CH3:5].O[Li].O>C1COCC1.O>[CH:26]1[C:27]2[C:22](=[C:21]([C:18]3[CH:19]=[CH:20][C:14]4[C:13](=[O:31])[NH:12][C:11]5[CH:32]=[C:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:33])=[O:2])[CH:8]=[CH:9][C:10]=5[NH:16][C:15]=4[CH:17]=3)[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: COC(=O)C(C)(C)c1ccc2c(c1)NC(=O)c1ccc(-c3cccc4cnccc34)cc1N2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)c1ccc2c(c1)NC(=O)c1ccc(-c3cccc4cnccc34)cc1N2
Temperature: 25 °C

Procedure:
A mixture of Example 806 (85 mg, 0.2 mmol) and LiOH.H2O(42 mg, 1 mmol) in THF (3 mL) and water (5 mL) was heated under reflux for 6 hours. After the reaction mixture cooled to room temperature, it was neutralized to pH=6. The solution was extracted with EtOAc three times, and combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to give the title compound. MS (ESI) m/e 424 (M+H)+, 1H NMR (DMSO-d6, 500 MHz): □ 9.85 (s, 1H), 9.56 (s, 1H), 8.55 (br s, 1H), 8.30 (dd, J=6.08, 3.28 Hz, 1H), 7.99 (s, 1H), 7.85-7.88 (m, 4H), 7.14 (d, J=1.87 Hz, 1H), 7.05 (s, 1H), 7.03 (dd, J=7.96, 1.72 Hz, 1H), 6.95 (d, J=1.25 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Cl:33][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:10]2([CH3:17])[CH2:9][CH2:8][C:7]3[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=3[CH3:34])[O:11]2)=[CH:25][CH:24]=1)[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)O2

Procedure:
0.48 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate was dissolved in a mixture of 5 ml of 99.5% ethanol and 2 ml of tetrahydrofuran. To this was added dropwise, under a nitrogen stream at 8°-10° C., a solution prepared by dissolving 133 mg of sodium hydroxide in 1 ml of 99.5% ethanol. When the whole of the solution had been added, the mixture was reacted for a further 18 hours at 0°-5° C., after which it was neutralized by adding to it dropwise a solution prepared by dissolving 0.37 g of concentrated hydrochloric acid in 1 ml of 99.5% ethanol. The solvent was then distilled off from the mixture under reduced pressure. The pale reddish oil thus separated was extracted with chloroform, and the chloroform extract was washed with water and then dried over anhydrous sodium sulfate. The crude product obtained by distilling the chloroform off under reduced pressure was subjected to silica gel column chromatography, and the desired 2-chloro-3-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]propionic acid was obtained from the fractions eluted with a 10:1 by volume mixture of benzene and ethyl acetate. Rf value on thin layer chromatography: 0.4 (tailing) [silica gel; developing solvent; benzene:99.5% ethanol=6:1 by volume]. Melting point 148°-149° C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: COc1ccnc(N)c1C#N
Reactant: O=CC(Br)CC(F)(F)F
Solvent: CCOCC
Solvent: CCO
Product: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Temperature: 156 °C
Yield: 19 %

Procedure:
A mixture of compound D3 (3.31 g, 22.19 mmol) and D4 (6.2 g, 21.86 mmol) in EtOH (10 ml) was subjected to microwave heating at 156° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was treated with Et2O and a solid precipitated. The solid was filtered off, washed with EtOAc and dried in vacuo to yield compound D5 (1 g, 18%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.Cl[C:19]1[N:24]=[N:23][C:22]([C:25]2[S:29][N:28]=[C:27]([CH3:30])[N:26]=2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:19]3[N:24]=[N:23][C:22]([C:25]4[S:29][N:28]=[C:27]([CH3:30])[N:26]=4)=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Product: Cc1nsc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)n1

Procedure:
5-(6-(4-(6-Fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-3-methyl-1,2,4-thiadiazole was prepared according to the procedure as described in Example 1, Method B, STEP 2, reacting 6-fluoro-1-(piperidin-4-yl)indoline as its corresponding HCl salt and 5-(6-chloropyridazin-3-yl)-3-methyl-1,2,4-thiadiazole, prepared as in STEP 1 above.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][CH:19]=1>O.S(=O)(=O)(O)O.CCOCC>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(C(O)CCc2ccccc2)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C(=O)CCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
14.9 g (0.05 mole) of potassium dichromate in a mixture of 50 ml of water and 10 ml of concentrated sulfuric acid were added to a solution of 34 g (0.14 mole) of 1-(3-methoxyphenyl)-3-phenylpropan-1-ol in 500 ml of ether while cooling with ice and stirred overnight at 20° C. The aqueous, green phase was separated and extracted twice with 100 ml of ether each time. The combined ether extracts were dried over sodium sulfate and the solvent was then removed in vacuo. 28.0 g (83%) of the compound 1-(methoxyphenyl)-3-phenylpropan-1-one were obtained as a yellow oil, which was reacted further without prior purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3.O[CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(O)(C(F)(F)F)=O>[C:55]([O:54][C:52]([N:49]1[CH2:50][CH2:51][CH:46]([O:44][C:41]2[CH:42]=[C:43]3[C:38]([CH2:37][N:36]4[C:32]([C:22]5[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:24][O:25][C:21]=5[CH3:20])=[N:33][N:34]=[C:35]43)=[CH:39][CH:40]=2)[CH2:47][CH2:48]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
Under nitrogen atmosphere, triphenylphosphine bound resin (1.22 g, 1.36 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30 minutes. 3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol (0.3 g, 0.91 mmol) (prepared as in Example 3, Step (a)), 4-hydroxy-boc-piperidine (0.27 g, 1.36 mmol, 1.5 eq.) and diethyl azodicarboxylate (0.21 ml, 1.36 mmol, 1.5 eq.) were added and the reaction was stirred at room temperature overnight. The resin was filtered off and washed with dichloromethane, methanol and ether. The combined organics were concentrated in vacuo. The residue was purified by alumina chromatography, eluting with dichloromethane 2% methanol/dichloromethane (0.5% methanol gradient), and was used without further purification in the next step. b) 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(piperidin-4-yloxy)-5H-[1,2,4]triazolo[3,4-α]isoindole 4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (466 mg, 0.91 mmol) was dissolved in TFA (5 ml) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated K2CO3 (aq). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by alumina chromatography, eluting with dichloromethane→5% methanol/dichloromethane (in 1% methanol gradient), to afford the title compound as a white solid (4 mg, 1% over 2 steps). 1H NMR (400 MHz, d4 MeOH) δ 7.53–7.43 (6H, m), 7.32 (1H, d, J=8.5 Hz), 7.08 (1H, dd, J=8.5, 2.4 Hz), 4.63–4.60 (1H, m), 4.24 (2H, s), 3.16–3.11 (2H, m), 2.85–2.79 (2H, m), 2.64 (3H, s), 2.09–2.05 (2H, m), 1.78–1.72 (2H, m). m/z (ES+) 414 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:17]=1[C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(OCC)(=O)C.ClCCl>[CH3:25][C:21]1[C:17]([C:18]([C:4]2[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])=[O:19])=[C:16]([O:15][CH3:14])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COc1cccc(C)c1C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)c2c(C)cccc2OC)c(OC)c1OC
Temperature: 0 °C

Procedure:
A mixture of 3,4,5-trimethoxytoluene (1.86 g; 10.2 mmol), 1B (10.2 mmol), aluminium chloride (1.33 g, 10 mmol) and dichloromethane (20 ml) is stirred at 0° C. The reaction sets up at 0° C. with formation of hydrogen chloride. Subsequently, the reaction mixture is stirred for another 4 hours at room temperature. A mixture of dilute hydrochloric acid and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at 0° C. The organic phase is concentrated and the residue is recrystallized from methanol. The solid material is collected by vacuum filtration, three times washed with methanol/water (3:1 v/v; 100 ml each) and dried yielding white crystals, 1.0 g (30.3%), mp 84° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[P:13]([O:18]C)([O:16][CH3:17])[O:14][CH3:15]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(C(C)(C)C)cc1)OC
Reaction time: 16 h
Yield: 95.2 %

Procedure:
4-t-Butylbenzyl bromide (19.16 g, 84 mmol) and trimethyl phosphite (10.46, 84 mmol) were heated at 120° C. under argon for 6 hours, after which a further 10.46 g trimethylphosphite was added and heating continued for a further 16 hours. The dimethyl methylphosphonate by-product was distilled off, leaving the desired dimethyl 4-t-butylbenzylphosphonate as a pale yellow oil (20.6 g, 80 mmol).