Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH2:16][CH3:17])=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:19]1([NH:22][C:23]([NH2:25])=[NH:24])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:19]1([NH:22][C:23]2[N:25]=[C:5]([C:7]3[C:8]([CH2:16][CH3:17])=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:24]=2)[CH2:21][CH2:20]1
Reactant: N=C(N)NC1CC1
Reactant: CCc1nn2ncccc2c1C(=O)/C=C/N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn2ncccc2c1-c1ccnc(NC2CC2)n1
Temperature: 135 °C
Yield: 36 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (75 mg, 0.31 mmol) in DMF (2.0 mL) was added N-cyclopropylguanidine.0.5H2SO4 (181 mg, 0.92 mmol) and potassium carbonate (212 mg, 1.54 mmol). The reaction was heated at an oil bath temperature of 135° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether and hexanes to give the title compound as an orange solid (32 mg, 36%). 1H-NMR (300 MHz, CDCl3) δ 8.96 (d, 1H, J=8.7 Hz), 8.38 (d, 1H, J=5.4 Hz), 8.34 (dd, 1H, J=4.4, 1.9 Hz), 7.14 (dd, 1H, J=9.0, 4.5 Hz), 6.92 (d, 1H, J=5.4 Hz), 5.47 (s, 1H), 3.23 (q, 2H, J=7.5 Hz), 2.88 (m, 1H), 1.50 (t, 3H, J=7.5 Hz), 0.91 (m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)+ 281.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH:24]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccc(F)cc1
Yield: 81.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (215 uL, 0.427 mmol) was treated with 4-fluorobenzeneboronic acid (26 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (42 mg, 81%). LC-MS m/e 425.28 (M+H+)
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:17]1([CH:23](Cl)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[C:17]1([CH:23]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(Cl)c1ccccc1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of phenoxazine 76 g, 0.417 mol (Aldrich Chemical Co., Milwaukee, WI, Cat. No. P1,585-8) in dry dimethylformamide (120 ml) was added to a stirred suspension of sodium hydride (22 g, 0.458 mol, 50% suspension in mineral oil) in dry dimethylformamide (500 ml). After 1 hour at room temperature α-phenylethyl chloride (59 g, 0.43 mol) was added dropwise and when the addition was completed, stirring was continued for another 30 min. The solution was poured into water, the product extracted with ethyl acetate, the extract washed with water, and dried over sodium sulfate. The solvent was removed under reduced pressure. N-α-Phenylethylphenoxazine was crystallized from ether-hexane, mp 100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.CN(C)C=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OC(c1cncnc1)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cncnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.8 %

Procedure:
The 5-[(2,5-difluorophenyl)-hydroxymethyl]pyrimidine (111 mg, 0.5 mmol) obtained in Referential Example 12 was dissolved in thionyl chloride (1.0 ml). A catalytic amount of dimethylformamide was added and the resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and the resulting mixture was concentrated further. The residue was dissolved in dimethylformamide (5 ml), followed by the addition of 4-chlorobenzenethiol (108 mg, 0.75 mmol) and potassium carbonate (414 mg, 3.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=4:1) to give a mixture (202 mg) of the title compound and an unidentified compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]#[C:15][C:16](=[O:33])[NH:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd]>[Cl:1][C:2]1[CH:13]=[C:12](/[CH:14]=[CH:15]\[C:16](=[O:33])[NH:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:19]([F:22])([F:20])[F:21])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5]
Reactant: O=C(C#Cc1ccc(C(=O)NC2CC2)c(Cl)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: O=C(/C=C\c1ccc(C(=O)NC2CC2)c(Cl)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
2-Chloro-N-cyclopropyl-4-[3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-prop-1-yn-1-yl]benzamide (110 mg, 0.20 mmol), quinoline (10 mg, 0.07 mmol) and palladium on calcium carbonate (5% Pd; 10 mg) were suspended in methanol and stirred for 4 days, in the course of which palladium on calcium carbonate (3×10 mg) was added again every 24 h. Then the reaction mixture was filtered through kieselguhr, and the filtrate concentrated to dryness under reduced pressure. The residue was purified by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 50% EA).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:63][C:62]=1[C:74]([F:77])([F:76])[F:75])([O-:60])=[O:59]>CN(C)C=O.ClCCl.O1CCCC1>[N+:58]([C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH:68]2[CH2:69][CH2:70][N:71]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:72][CH2:73]2)=[CH:63][C:62]=1[C:74]([F:77])([F:75])[F:76])([O-:60])=[O:59]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 3), diisopropylethyl amine (25 μL; 0.15 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (19 mg; 0.03 mmol). The structure was confirmed using Protocol I-C. Calculated mass=588; observed mass=588; HPLC retention time=3.03 min.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH:24]=1
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
LiHMDS (1.0M in THF, 62 mL, 6.2 mmol) was added dropwise to a stirred solution of pyridin-2-ylamine (3.1 g, 33 mmol) in anhydrous THF (50 mL) under a nitrogen atmosphere at −78° C. After 30 min stirring at −78° C., 2,4-difluoro-1-nitrobenzene (3.4 mL, 31 mmol) was added and stirring at −78° C. continued for 30 min. The reaction mixture was slowly warmed to RT and after 5 h quenched by addition of a saturated aqueous solution of NH4Cl (150 mL). The mixture was partitioned between EtOAc and water, then filtered through Celite®. The organic fraction was dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% DCM in cyclohexane) to afford the title compound as an orange solid (3.9 g, 54%). 1H NMR (CDCl3, 400 MHz): δ 10.48 (1H, s), 8.82 (1H, dd, J=12.32, 2.77 Hz), 8.38 (1H, dd, J=5.03, 1.87 Hz), 8.34-8.25 (1H, m), 7.70-7.64 (1H, m), 7.03-6.94 (2H, m), 6.68-6.61 (1H, m).
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:15]2[C:5](=[CH:6][C:7]3[CH:8]4[CH2:18][CH:12]([C:13]=3[CH:14]=2)[CH2:11][NH:10][CH2:9]4)[N:4]=1.ClC1C=CC2C(=CC3C4CC(C=3C=2F)CNC4)N=1>>[CH:8]12[CH2:18][CH:12]([CH2:11][NH:10][CH2:9]1)[C:13]1[CH:14]=[C:15]3[C:5]([NH:4][C:3](=[O:2])[CH:17]=[CH:16]3)=[CH:6][C:7]2=1
Reactant: COc1ccc2cc3c(cc2n1)C1CNCC3C1
Agent: Fc1c2c(cc3nc(Cl)ccc13)C1CNCC2C1
Product: O=c1ccc2cc3c(cc2[nH]1)C1CNCC3C1

Procedure:
6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11)),3,5,7,9-pentaene; 6-methoxy-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene; 6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2].S(Cl)([Cl:22])=O>CN(C=O)C>[C:1]([O:4][C:5]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][C:8]([C:9]([Cl:22])=[O:10])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)C)cc(C(=O)Cl)cc1C(C)C

Procedure:
A mixture of 4-acetoxy-3,5-diisopropylbenzoic acid (634 mg), thionyl chloride (3 ml) and DMF (1 drop) was refluxed for 40 minutes, concentrated and evaporated to obtain 4-acetoxy-3,5-diisopropylbenzoyl chloride. The resultant was dissolved in dichloromethane (20 ml), to which 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (566 mg) and triethylamine (0.30 ml) were added. Thus obtained solution was stirred at room temperature for one night. After dilution with water, the solution was extracted with dichloromethane. The dichloromethane layer was washed with 2N-hydrochloric acid and water, and then dried (MgSO4). The solvent was removed and the residue was recrystallized from ethanol to obtain 3-(4-acetoxy-3,5-diisopropylbenzamido)-4-(2-chlorophenyl)-6,8-dimethylquinoline (815 mg, 77.0%) as colorless prisms.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl.FC(F)(F)C(O)=O>[NH2:44][C@H:45]([CH:46]([CH3:48])[CH3:47])[C:49]([N:31]([CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:9][C:10]=3[F:36])[CH:21]=2)=[CH:29][CH:28]=1)[CH2:32][CH2:33][O:34][CH3:35])=[O:50]
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)[C@H](N)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.2 %

Procedure:
To a solution of 339 (48 mg, 0.095 mmol), N-Boc-valine (41 mg, 0.19 mmol), and DIPEA (0.083 mL, 0.47 mmol) in DMF (20 mL) was added HATE (90 mg, 0.236 mmol). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was partitioned between ethyl acetate and water, washed with 1M HCl and brine, dried (MgSO4), filtered and concentrated to yield the crude, BOC-protected product. This material was dissolved in dichloromethane (75 mL) and trifluoroacetic acid (3 mL), and stirred at r.t. for 3 h. The mixture was then concentrated and the residue was purified by Gilson reverse phase HPLC (35-95% MeOH/H2O, Aquasil C18, 30 min) and lyophilized. The residue (containing some formic acid from the HPLC) was partitioned between dichloromethane and 1M NaOH. The organic phase was dried (MgSO4), filtered and concentrated to give 341 (18 mg, 50% yield) as a 7:3 mixture of rotamers by 1H NMR. 1H NMR (DMSO-d6) δ (ppm) 1H: 8.73 (s, 1H); 8.57-8.51 (m, 2H); 8.36 (s, 0.3H); 8.32 (s, 0.7H); 8.29-8.24 (m, 1H); 7.84-7.71 (m, 2H); 7.38 (t, J=8.8, 1H); 7.21 (d, J=8.3, 1H); 6.66-6.64 (m, 1H); 6.59 (s, 1H); 4.90 (d, J=17.6, 0.3H); 4.73 (d, J=15.6, 0.7H); 4.64 (d, J=17.1, 0.3H); 4.53 (d, J=15.6, 0.7H); 3.73-3.39 (m, 5H); 3.25 (s, 2.2H); 3.22 (s, 1H); 2.58-2.52 (m, 1H); 1.80-1.70 (m, 1H); 0.89-0.84 (m, 6H); 0.68-0.64 (m, 2H); 0.45-0.41 (m, 2H). LRMS: (M+H) 607.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:21][C:13]3[NH:12][C:20]4[C:15]([CH:14]=3)=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A mixture of 6-chloro-2-oxindole (41 mg) (commercially available), indole-2-carbaldehyde (42 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was held in a sealed tube at 95° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven to give 62 mg (87% yield) of 6-chloro-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one as a shiny orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[H-].[Na+].C1(C)C=CC(S(O[CH2:33][CH2:34][O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=O)=O)=CC=1>CN(C=O)C>[CH:36]1([O:35][CH2:34][CH2:33][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:19][CH3:20])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCOC1CCCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
7-Hydroxy-6-methoxy-4-phenoxyquinazoline (1.11 g, 4.2 mmol), (prepared as described for the starting material in Example 16), in DMF (1 7 ml) was added to a suspension of sodium hydride (184 mg of a 60% suspension in oil, 4.6 mmol) in DMF (3 ml). The mixture was stirred until evolution of gas ceased, and then 2-cyclopentyloxyethyl 4-toluenesulphonate (1.25 g, 4.45mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at ambient temperature for 30 minutes, then heated at 60° C. for 2 hours, and then at 80° C. for a further 4 hours before being allowed to cool. The mixture was poured onto ice and extracted with methylene chloride. The combined extracts were washed with brine, passed through phase separating paper and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate. The purified product was triturated with isohexane to give 7-(2-cyclopentyloxyethoxy)-6-methoxy-4-phenoxyquinazoline (480 mg, 28%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=1>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44](=[O:45])[CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][NH:35][CH2:34][CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[CH:42][CH:41]=3)=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1
Product: O=C(Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
The synthesis was carried out analogously to Example XVe), starting [lacuna] 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 110 mg of {4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid. This gave the product of molecular weight 733.82 (C40H45F2N3O8+); MS (ESI) 734.32 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:15]([CH:16]=C)[CH2:14][O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.I([O-])(=O)(=O)=[O:19].[Na+]>C(O)CCC.CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH:16]([CH:15]1[C:4]2[C:5](=[C:6]3[C:11](=[C:2]([CH3:1])[CH:3]=2)[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3)[O:13][CH2:14]1)=[O:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC1COc2c1cc(C)c1[nH]c(=O)ccc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: CC(C)=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OCC2C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
5-Methyl-2,3,6,7-tetrahydro-3-vinylfuro[2,3-f]quinoline-7-one (1.75 g) was dissolved in a mixture of butanol-acetone-water (3:3:1, 350 ml), to which sodium periodate (11.5 g) and osmium tetraoxide (350 mg) were added, followed by stirring at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was subjected to distillation to remove the solvent. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 1.05 g of 3-formyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow needles (59.5%).
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@@H:29]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[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@@H:29]([CH2:35][C:36]([N:38]([CH3:39])[CH3:40])=[O:37])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)C[C@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CC(=O)N(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.95 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 69-2 (6.96 mmol, crude form) as starting materials, respectively 0.92 g (Isomer A: colorless powder) and 1.48 g (Isomer B: colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[OH:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][OH:34]>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:29][OH:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 300 g. of sodium 4-acetylbenzenesulfonate is added in portions to a well-stirred, cooled solution of 500 ml. of bis(2-hydroxyethyl)amine in 750 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled to 0°-5° C. and the precipitate of 4-acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide is collected by filtration and crystallized from water; m.p. 87.5°-89.5° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]=1[CH3:44])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl>[C:52]([O:21][C:20]1[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:16]([CH3:44])[C:17]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:18]([O:24][CH3:25])[C:19]=1[O:22][CH3:23])(=[O:54])[CH3:53]
Reactant: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(CCCCCCCCCCOC(C)=O)c(OC(C)=O)c1OC
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
6-(10-Acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol (0.65 g) was dissolved in dichloromethane (5 ml), and triethylamine (0.2 ml) followed by acetyl chloride (0.08 g) was added. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated, and then the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (9:1) to obtain the desired compound (0.483 g).