Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:34](OC)=[O:35])[CH2:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:38][OH:39]>O1CCCC1.CO>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([NH:15][CH:16]([CH2:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:34]([NH:38][OH:39])=[O:35])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)NC(=O)CNC(=O)OCc1ccccc1
Reactant: NO
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.2 %

Procedure:
To a solution of the title compound of Example 16b (440 mg, 0.81 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added NH2OH (50% aqueous solution, 0.74 mL, 12 mmol). After stirring for 20 hours at room temperature, the solution was concentrated. Purification by flash chromatography (5:95 MeOH/CHCl3) yielded the title compound as a white solid (80 mg, 18%): Anal. Calcd. for C25H25N3O7S2.0.25 H2O: C, 54.78; H, 4.69; N, 7.67; S, 11.70. Found: C, 54.78; H, 4.72; N, 7.46; S, 11.53.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][N:13]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][NH2:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C

Procedure:
A solution of 188 mg (0.55 mmol) of tert-butyl{(4S)-5-azido-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 85A) in ethanol is hydrogenated after the addition of 20 mg of palladium on activated carbon (10%) at RT under atmospheric pressure for 12 h. The mixture is filtered through kieselguhr, and the residue is washed with ethanol. The filtrate is evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [CH2:1]([C:9]1[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[CH2:13][CH3:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](Cl)(=O)[C:29](Cl)=O.[CH3:34][N:35](C=O)C>C(Cl)Cl>[CH2:34]([NH:35][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([N:12]([CH2:13][CH3:14])[CH2:11][C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]=2[CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][CH:22]=1)[CH2:28][CH3:29]
Reactant: CCN(Cc1ccccc1CCc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(N(CC)Cc2ccccc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[N-(2-(Phenethyl)benzyl)-N-ethylamino]benzoic acid (1.5 g), oxalyl chloride (0.43 ml), DMF (0.1 ml) and CH2Cl2 (50 ml) were stirred together for 2 hours. The solvent was evaporated and the residue re-dissolved in dichloromethane (100 ml). This was added to a solution of propylamine (0.35 ml) in dichloromethane (10 ml) at 0° C. The resulting mixture was stirred for 2 hours at ambient temperature, filtered and the filtrate purified by MPLC, eluting with ethyl acetate to give a gum. The gum was purified by crystallisation from diethyl ether/iso-hexane to give N-propyl-4-[N-ethyl-N-(2-(phenethyl)benzyl)-amino]benzamide (0.3 1 g) as a white solid, (mpt. 91/93° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[Br:12]Br.CO.O>C(O)(=O)C>[NH2:11][C:3]1[C:2]([OH:1])=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Nc1c(O)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
3-Hydroxyanthranilic acid (6.28 g, 41.0 mmol) was dissolved in acetic acid (550 ml), then a solution of bromine (13.1 g, 82.0 mmol) dissolved in acetic acid (50 ml) was gradually and dropwise added at room temperature, taking 20 minutes. After stirring at room temperature for 2.5 hours, methanol (70 ml) and water (300 ml) were added to the solution, followed by stirring at room temperature for 15 hours. The formed solid was collected by nitration, and dried under reduced pressure to obtain the entitled compound (9.129 g, 97%) as a brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br/C(=C\C)/C(O)=O.CNC.IC1C=C(NC2C3C(=CC=C(N[C:49](=[O:56])[CH:50]=[CH:51][CH2:52][N:53]([CH3:55])[CH3:54])C=3)N=CN=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:49](=[O:56])[CH:50]=[CH:51][CH2:52][N:53]([CH3:55])[CH3:54])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(I)c3)c2c1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: C/C=C(\Br)C(=O)O
Agent: CNC
Product: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
4-[(3-bromophenyl)amino]-6-aminoquinazoline is reacted with bromocrotonic acid and dimethylamine, as is described hereinabove in Compound 5, to give N-{4-[(3-bromophenyl)amino]quinazoline-6-yl}4-(dimethylamino)-2-butenamide.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[OH:8][C:1]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[CH2:13][CH2:14]1
Reactant: Br[Mg]c1ccccc1
Reactant: N#Cc1ccc(OCCCN2CCC(C(=O)c3ccccc3)CC2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 6 h
Yield: 69.8 %

Procedure:
4-(3-(4-Benzoylpiperidin-1-yl)propoxy)benzonitrile (0.5 g, 1.4 mmol) was dissolved in dry THF (˜15 mL), and a solution of phenylmagnesium bromide (0.9 mL, 2M, 1.8 mmol) was added and the reaction stirred for 6 h. The reaction was quenched (sat. NH4Cl) and extracted into EtOAc (2×). The organic layers were dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified on silica gel (EtOAc/hexanes) to give 417 mg (70% yield) of title compound Example B1: 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, d, J=8.8 Hz), 7.50 (4H, d, J=7.6), 7.30 (4H, q, J=8), 7.20 (2H, t, J=7.2 Hz), 6.94 (2H, d, J=8.8 Hz), 4.06 (2H, t, J=6 Hz), 3.07 (2H, d, J=11.2 Hz), 2.59 (2H, t, J=7.2 Hz), 2.53-2.46 (1H, m), 2.14-2.01 (4H, m), 1.66-1.55 (4H, m), LC-MS (>98%) m/z=427.0 [M+H]; HRMS=427.2386 [M+H], 100% calculated for C28H31N2O2, 427.2386.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:25]OS([O-])=O.[K+]>CO.C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])(=[O:25])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-{[4-(2-butynyl oxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide (180 mg, 0.52 mmol) in MeOH/THF at room, oxone (5.0 g, excess) was added in water (20 ml). Reaction mixture was stirred at room temperature for 6 hrs and filtered. Methanol-THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography by eluting it with 4:1 ethyl acetate; hexane and 2-{[4-(2-butynyloxy) phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide was isolated as a white solid. mp: 191° C.; Yield: 45 mg (24%); MS: 366.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ0.95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J=2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J=9.1 Hz, 1H), 4.87 (d, J=2.34 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.76 (d, J=9 Hz, 2H), 9.01 (s, 11H), 10.7 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.94 g, 5.17 mmol) in acetonitrile (11 mL) was treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol) and acetonitrile (11 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 4.71 mmol) in acetonitrile (11 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 52%) as a red/orange oil: HR-ES-MS m/z calculated for C17H19NO4FCl [M+H]+ 356.1060, observed 356.1060; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.36-1.54 (m, 1H), 1.62 (ddd, J=14.0, 9.6, 4.6 Hz, 1H), 1.81 (ddd, J=14.0, 11.4, 4.6 Hz, 1H), 3.66 (s, 3H), 4.22 (d, J=18.3 Hz, 1H), 4.28 (d, J=18.3 Hz, 1H), 4.74 (dd, J=11.4, 4.6 Hz, 1H), 5.07 (s, 1H), 7.33 (td, J=8.1, 1.4 Hz, 1H), 7.48-7.55 (m, 1H), 7.58 (ddd, J=8.1, 6.7, 1.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][N:11]=1.C(N(CC)CC)C.O>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][N:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2nc(Cl)ncc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A solution of p-toluidine (46.9 g) in DMF (100 ml) was added dropwise to a solution of 2,4-dichloro-5-pyrimidinecarboxamide (80 g) and triethylamine (63.9 ml) in DMF (300 ml) with ice cooling. The mixture was stirred for 2 h allowing to warm to room temperature, then added to water (1 l) and stirred for 20 min. The slurry was filtered and the solid washed with water. The solid was suspended in a mixture of methanol (500 ml) and ether (500 ml), stirred for 20 min and filtered to give 2-chloro-4-[(4-methylphenyl)amino]-5-pyrimidinecarboxamide as pale yellow solid (94.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[CH:5]=[N:6][C:7]=1[OH:8].I[CH:13]([CH3:15])[CH3:14].[C:16]1(C)[CH:21]=CC=C[CH:17]=1>C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH:16]([CH3:21])[CH3:17])=[O:10])[CH:5]=[N:6][C:7]=1[O:8][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: Cc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Chloro-6-hydroxy-3-pyridinecarboxylic acid (1 g, 5.76 mmol) was suspended in toluene (200 ml) and treated with silver carbonate (3.97 g, 14.40 mmol) and 2-iodopropane (3.46 ml, 34.6 mmol) and stirred at RT in the dark for 3 days. Added further 2-iodopropane (3 ml) and stirred for 24 hours. Added EtOAc (200 ml) and washed with water (200 ml) and saturated NaHCO3 (50 ml) followed by water (200 ml). Dried over MgSO4 and evaporated off the solvent to yield 1.0 g of the title compound as a clear, colourless oil used without further characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[C:10]([S:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([S:14][C:15](=[O:20])[CH:16]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:17](=[O:19])[CH3:18])([CH3:13])([CH3:11])[CH3:12]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Br)cc1)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 11a using 1-bromo-4-bromomethylbenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([Cl:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[CH3:30])[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:31](Cl)(=[O:34])[CH2:32][CH3:33].O>N1C=CC=CC=1.Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([Cl:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[CH3:30])[C:6](=[O:9])[CH2:7][O:8][C:31](=[O:34])[CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 1 h

Procedure:
A solution of 17-acetoxy-11β-chloro-21-hydroxy-16β-methylpregna-1,4-diene-3,20-dione (67 mg.) in pyridine (1 ml.) at 0° was treated with propionyl chloride (0.03 ml.). After one hour, a little water was added and the solution was diluted with dilute hydrochloric acid. The precipitated solid was collected and recrystallized from methanol to give the title compound, m.p. 213°-215° (K), [α]D + 108.4° (c 0.6, chloroform) λmax 240 nm (ε 15,760) (Found: C, 65.9; H, 7.2. C27H35Cl O6 requires C, 66.0; H, 7.2).
Reaction SMILES: [CH3:1][C:2]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[C:4]12([C:2](=[O:3])[CH:1]=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Product: CN(C)C=CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 37 %

Procedure:
A solution of 17.83 g (0.10 mol) of 1-adamantyl methyl ketone in 35.75 g (0.30 mol) of dimethylformamide dimethylacetal was heated at reflux for 24 hours. After cooling and removal of the solvent in vacuo at 45° to 50° C., the residue was purified by silical gel chromatography to yield 8.64 g (37%) of a white solid: Rf 0.20 in 50% EtOAc/Ligroin; 1H NMR (CDCl3) δ 1.68 (S, 6H, the δ hydrogens of the adamantyl ring, methylene protons at the farthest position from the substituent), 1.81 (S, 6H, the β hydrogens of the adamantyl ring, methylene protons at the closest position to the substituent), 2.00 (S, 3H, the three bridgehead protons, 2.90 (br S, 6H, N(CH3)2), 5.20 (d, 1H, J=14 Hz, O=C-CH), 7.60 (d 1H, J=14 Hz, =C-N<). All analytical data confirmed the assigned structure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:50])[O:12][C:13]([OH:49])([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]=[N+]=[N-])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:50])[O:12][C:13]([OH:49])([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH2:38])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OCCOCCOCCOCCN=[N+]=[N-])c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OCCOCCOCCOCCN)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
A mixture of 1.49 g (2.15 mmol) of 3-Benzo[1,3]dioxol-5-yl-4-(3-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethoxy)-4,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one 9 and 1.00 g (3.00 mmol) of polymer bound PPh3 (polystyrene, 2% DVB, FLUKA) was suspended in 10 ml of THF and stirred at room temperature overnight. Water is added (200 μl, ≈10 mmol) and stirring was continued for 3 d. The polymer was removed by filtration and the filtrate was evaporated in vacuo. The remaining oil was purified by silica gel column chromatography (EtOAc/MeOH/NEt3 5/1/0.3), yielding 246 mg of the product (0.37 mmol, 17%). 1H-NMR (CDCl3) δ=7.32 (d, 2H, J=8.1 Hz), 6.83, (m, 2H), 6.75 (d, 2H, J=8.1 Hz), 6.68 (d, 1H, J=7.7 Hz), 6.14 (s, 1H), 5.91 (s, 1H), 5.85 (s, 2H), 3.88 (m, 2H), 3.70 (s, 4H), 3.64 (s, 3H), 3.59 (m, 4H), 3.54 (s, 3H), 3.48 (m, 4H) 3.37 (m, 2H), 3.15 (m, 2H) ppm. The protons of the butenolide hydroxy group and the amino function were not detected. 13C-NMR δ=171.2, 160.8, 160.1, 152.8, 151.9, 147.9, 147.5, 137.2, 131.8, 129.2, 127.8, 127.4, 123.2, 123.1, 113.7, 109.4, 108.5, 108.2, 106.6, 106.0, 101.2, 70.6, 70.4, 70.3, 70.2, 69.8, 69.7, 68.6, 60.6, 55.8, 55.2, 40.0, 32.0 ppm. MS: m/z=690 [M+Na]+, 668 [M+H]+. Elemental or HRMS analysis could not be obtained from this product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:10]=[C:9]([NH2:11])[NH:8][N:7]=1.CN1CCOCC1.O>C(Cl)Cl>[CH3:5][C:6]1[CH:10]=[C:9]([NH:11][C:1](=[O:3])[CH3:2])[NH:8][N:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(N)[nH]n1
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)Nc1cc(C)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Acetyl chloride (41 g, 0.530 mol) was added dropwise to a solution of 3-methyl-1H-pyrazol-5-amine (25.6 g, 0.264 mol) and N-methylmorpholine (58 mL, 0.530 mol) in CH2Cl2 (250 mL) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 h. Water was added to the reaction mixture and the organic layer concentrated in vacuo. The residue was taken up in a mixture of MeOH/THF (100 mL/100 mL), cooled to 10° C. and treated with 1M NaOH solution. The reaction mixture was stirred for 0.25 h, acidified to pH 5 and organic solvents were removed in vacuo. The resulting precipitate was filtered, washed (water, diethyl ether) and dried to provide the title compound as a white solid (29.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:21]=2[N:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][C:21]=4[N:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1nc2cc(-c3ccccc3)ccc2o1
Product: c1ccc(-c2ccc3oc(COc4ccc(CCCn5ccnc5)cc4)nc3c2)cc1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-chloromethyl-5-phenylbenzoxazole to give 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-phenylbenzoxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave pale yellow plates, mp 123-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](C#N)=[N:6][CH:7]=1.[CH3:10][Mg]Br.Cl.[C:14](=[O:17])(O)[O-].[Na+]>C(OCC)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14](=[O:17])[CH3:10])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: N#Cc1ccc(Cl)cn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Cl)cn1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
5-Chloropyridine-2-carbonitrile (10.71 g, 77 mmol) was dissolved in diethylether (65 mL) and THF (35 mL) under a nitrogen atmosphere. The mixture was cooled until the internal temperature was −63° C. Methyl magnesium bromide (3M in THF, 35 mL, 105 mmol) was added over 30 min. The reaction mixture was then left stirring at −60° C. for 45 min and was then warmed to room temperature. 50 mL of THF was added to dissolve any precipitated material. After 1 h at room temperature the reaction was judged complete by HPLC. 2M hydrochloric acid (aq., 100 mL) was added and the reaction mixture was stirred for 4 h. pH was adjusted to 7 with sodium bicarbonate. The phases were separated and the product extracted from the aqueous phase twice with DCM. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The product was purified by column chromatography (eluent heptane: ethyl acetate gradient) to yield 7.9 g (64% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.79 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.98 (d, 2H, J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H, J=7.7 Hz, J=1.5 Hz), 7.16 (m, 2H), 2.60 (s, 3H), 2.36 (s, 3H). MS: m/z 429 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Cl[CH2:14][C:15]1[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:14][C:15]3[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)o1
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1ccc(C(F)(F)F)o1
Yield: 87 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (659 mg) was reacted with 2-(chloromethyl)-5-(trifluoromethyl)furan as in General Procedure 1 to give the title compound as a beige solid (87% yield). M.p. 189-191° C., LCMS: m/z=424.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.21 (s, 2H), 4.95 (bs, 1H), 5.05 (s, 2H), 6.39 (s, 1H), 6.75 (s, 1H), 7.50 (s, 1H), 7.96 (s, 1H).