Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16](C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=[CH:40][C:39]([C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[CH:38][CH:37]=1.C(OC(=O)C(NN1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)C>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[C:16]([C:44]1[O:43][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:37][CH:38]=2)=[CH:46][CH:45]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reactant: c1ccc(-c2ccc(-c3ccco3)cc2)cc1
Agent: CCOC(=O)C(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 57 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)ethane-1,2-dione, 2-biphenyl-4-yl-furan was deprotonated and alkylated with N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-oxamic acid ethyl ester to give in 57% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)ethane-1,2-dione as a pale yellow amorphous solid. 1H NMR: δ 7.91 (d, 2H, J=8.1 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.64 (d, 2H, J=8.1 Hz), 7.49-7.36 (m, 4H), 7.25-7.10 (m, 5H), 6.85 (d, 1H, J=4.0 Hz), 4.62-4.57 (m, 1H), 3.91 (m, 2H), 3.00 (dd, 1H, J=5.0, 13.0 Hz), 3.82 (dd, 1H, J=10.1, 13.2 Hz), 1.86 (s, 3H), 1.68 (s, 3H). Anal. Calculated for C30H27NO4 : C, 77.40; H, 5.85; N, 3.01. Found: C, 77.43; H, 5.88; N, 3.06.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][CH2:17][CH3:18].[Na+].C([OH:22])C>>[O:8]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([O:15][CH2:17][CH3:18])=[O:22]
Reactant: CC[O-]
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: CCO
Agent: [Na+]
Product: CCOC(=O)CCCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2-benzoylcyclohexanone (1.00 g), sodium ethoxide (404 mg) in ethanol (5 mL) was stirred for 3.5 hours at room temperature. The reaction was quenched by adding 1N hydrochloric acid (1 mL). The solvent was evaporated off, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give ethyl 7-oxo-7-phenylheptanoate as a brown oil (1.33 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cccc(F)c1

Procedure:
Prepared according to Procedure A using 3-fluoroaniline (18 mL, 187 mmol), pyridine (31 mL, 374 mmol) and diethyl methylmalonate (48 mL, 281 mmol). The crude was purified by column chromatography on silica (using a gradient of hexanes:EtOAc, 1:0 to 3:1 as eluant) to give ethyl 3-(3-fluorophenylamino)-2-methyl-3-oxopropanoate as a light brown solid. Mass Spectrum (ESI) m/e=240.1 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O.C(O)C>C1(C)C=CC=CC=1.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:5]3=[N:4][C:3]=2[C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(-c2nc3ncccn3c2Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
0.225 g (0.74 mM) 4-(3-bromoimidazo[1,2-a]pyrimidin-2-yl)benzaldehyde is dissolved in 5 mL of toluene. To this mixture is added 4-fluorphenyl boronic acid (1.5 eq) followed by tetrakis triphenylphosphine palladium (0) 10% by wt, K2CO3 (3 eq) and ethanol water mixture (4 mL). The reaction mixture is heated at 90° C. for 4-6 h. The reaction is cooled to room temperature and 20 mL of water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is dried and concentrated. The crude is purified by flash column chromatography to yield the desired compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13][C:14]([CH2:16]Br)=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[NH2:18][C:19]([NH2:21])=[S:20].[ClH:22]>C(O)CC>[CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13][C:14]3[N:18]=[C:19]([NH2:21])[S:20][CH:16]=3)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[ClH:22]
Reactant: NC(N)=S
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCCO
Product: Nc1nc(CCN2C(=O)c3ccccc3C2=O)cs1

Procedure:
1-Bromo-4-N-phthalimido-2-butanone (50.0 g, 0.169 mol) and thiourea (25.71 g, 0.338 mol) were mixed with n-propanol (1000 ml) and concentrated hydrochloric acid (100 ml), and the reaction mixture was heated to reflux for 1.5 hour. After cooling, the precipitate was filtered and washed with n-propanol and ether. After air drying, the title product was obtained as a fluffy white solid (37.51 g, 0.121 mol, 72% yield), m.p. 230°-240° (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:18](=[O:19])[CH2:17][C:15]([OH:16])=[O:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccc(Br)cc1C(=O)O
Yield: 80.4 %

Procedure:
5-Bromoanthranilic acid (0.30 g, 1.4 mmol) was added to a solution of Meldrum's acid (0.24 g, 1.7 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and the suspension was heated to reflux for 3 h. The suspension was cooled, filtered, washed with toluene and dried. Crude 5-bromo-2-[(carboxyacetyl)amino]benzoic acid (0.34 g, 81%) was obtained as a colourless solid; mp 203-206° C.; δH (500 MHz, DMSO-d6) 3.48 (s, 2H, CH2), 7.78 (d, J3,4=8.4 Hz, 1H, H4), 8.04 (s, 1H, H6), 8.40 (d, J3,4=8.4 Hz, 1H, H3), 11.20 (s, 1H, NH), 12.80 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 44.7, 114.5, 119.4, 122.5, 133.1, 136.4, 139.4, 164.7, 167.8, 168.9; νmax 1224, 1373, 1520, 1683, 2985 cm−1.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3]1.O.[OH-].[Li+:23]>O1CCOCC1.CO.O>[CH3:1][C@@H:2]1[N:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O-:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[Li+:23]
Reactant: COC(=O)c1cccc2oc(N3CCOC[C@@H]3C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc2c(C(=O)[O-])cccc2o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-methyl 2-(3-methylmorpholino)benzoxazole-4-carboxylate (0.58 g, 2.1 mmol) in 1,4-dioxane/CH3OH/H2O (2:2:1, 8.5 mL) containing lithium hydroxide monohydrate (150 mg, 6.30 mmol) was stirred at room temperature 24 h. The reaction mixture was concentrated under reduced pressure and residual H2O was azeotropically removed with benzene (2×100 mL) to yield lithium (S)-2-(3-methylmorpholino)benzoxazole-4-carboxylate as a white solid which was used in the next step without further isolation or purification.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH:28][C:29](=[O:42])[C@H:30]([C:35]([S:38]([CH3:41])(=[O:40])=[O:39])([CH3:37])[CH3:36])[NH:31][C:32](=[S:34])[NH2:33])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][CH:46]=O>C(O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH:28][C:29](=[O:42])[C@H:30]([C:35]([S:38]([CH3:41])(=[O:40])=[O:39])([CH3:37])[CH3:36])[NH:31][C:32]1[S:34][CH:45]=[CH:46][N:33]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(N)=S)C(C)(C)S(C)(=O)=O
Reactant: O=CCCl
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Nc1nccs1)C(C)(C)S(C)(=O)=O
Yield: 38 %

Procedure:
A stirred solution of 255 mg (0.4 mmol) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(thiocarbamoyl)-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide in 5 ml of ethanol was treated with 0.1 ml of chloroacetaldehyde (50% solution in water) and heated at reflux for 4 hours. The volatiles were evaporated and the residue partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane and the combined organic phase was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a solid which was chromatographed on silica eluting with dichloromethane/methanol (19:1) to give 100 mg (38%) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(2-thiazolyl)-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide as a white solid, [M+H]+ 662.2.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]>ClCCl>[CH2:13]([Cl:1])/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Reaction time: 0.22 h
Yield: 103.8 %

Procedure:
A solution of N-chlorosuccinimide (6.8 g, 50.9 mmol) in dry dichloromethane (338 ml) was cooled to -30 ° and dimethylsulfide (4.1 ml, 55.3 mmol) was added dropwise over 3 min. After 13 min., the cooling bath was removed and the mixture was stirred for 30 min. The mixture was cooled to -40 ° and a solution of (E,E)-farnesol (11.3 ml, 44 mmol) in 112 ml dichloromethane was added over 10 min. The cooling bath was removed and the mixture was stirred for 30 min. The temperature of the reaction mixture rose to 0° and a clear solution was obtained. After stirring for two more hours the solvent (about 400 ml) was removed on a rotary evaporator and the material was taken up in hexane (600 ml). The solution was washed with ice cold water (3×90 ml) and cold brine (2×35 ml) and then dried (MgSO4). The solvent was removed under vacuum at ambient temperature and finally dried under pump vacuum to give 11.0 g (100%) of title compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][SH:2].C(N(CC)CC)C.[Cl:10][C:11](Cl)=[C:12]([Cl:16])[C:13]([O-])=O.[CH3:18][OH:19]>>[CH3:18][O:19][C:1](=[S:2])[C:11]([Cl:10])=[C:12]([Cl:16])[CH3:13]
Reactant: CO
Reactant: CS
Reactant: O=C([O-])C(Cl)=C(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=S)C(Cl)=C(C)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.85 gms (92 mmols) of methanethiol and 9.3 gms (92 mmols) of triethylamine in methanol was slowly added to 17.6 gms (92 mmols) trichloroacrylate with cooling. After addition, the reaction system was stirred at room temperature for about 20 hours. The solvent and excess methanethiol were removed under reduced pressure. Ether was added to the residue (crude product) and the precipitated solvents filtered. The ether was removed under reduced pressure to give an oil. The oil was distilled to give 11.6 gms of a low melting solid (boiling point 125°-150° C. at approximately 50 mm Hg; melting point 27°-30° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[NH2:17][C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].C(N(CC)CC)C>CN(C=O)C>[N+:13]([C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:17]([C:18]1([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:5]2=[O:7])([O-:15])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a stirred mixture of 18 (0.25 g, 0.912 mmol) and 4 (0.337 g, 0.912 mmol) in DMF (3.0 mL) was added triethylamine (0.320 mL, 2.28 mmol) and resulting mixture was stirred at 114° C. to 130° C. After 18 h, the mixture was cooled and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 19 (0.27 g, 60%) as a light brown fluffy solid. 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.45 (d, J=8.2 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.80 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.44-7.19 (m, 5H), 5.17-4.84 (m, 4H), 3.05-2.96 (m, 2H), 2.69-2.52 (m, 3H), 2.20-1.94 (m, 3H), 1.35 (m, 4H). MS (ESI) m/z calcd for C25H27N4O7 [M+H]+ 495.5, found 495.9.
Reaction SMILES: CS(O[N:6]=[C:7](Cl)[C@H:8]1[CH2:12][O:11][C:10]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9]1)(=O)=O.[N:19]1C=CC=CC=1.[S-:25][C:26]#[N:27].[Na+].BrC1C=C(OC2C(C)=NC=CC=2)C(N)=NC=1>C(#N)C>[O:9]1[C:10]2([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[O:11][CH2:12][CH:8]1[C:7]1[N:6]=[C:26]([NH2:27])[S:25][N:19]=1
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: N#C[S-]
Reactant: c1ccncc1
Agent: Cc1ncccc1Oc1cc(Br)cnc1N
Agent: [Na+]
Solvent: CC#N
Product: Nc1nc(C2COC3(CCCCC3)O2)ns1
Temperature: 40 °C
Yield: 28.5 %

Procedure:
(R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (1.86 g, 6.25 mmol), pyridine (1.13 g, 14.3 mmol) and sodium thiocyanate (0.58 g, 7.14 mmol) were dissolved in acetonitrile (45 mL). The solution was heated to 40° C. for 40 minutes. 5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (1.0 g, 3.57 mmol) was added and the reaction was heated at 60° C. overnight. The solution was cooled to 0° C., filtered and the solid was dried to give (S)-N-5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.90 g, 1.78 mmol, 50% yield) as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:37])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:38])[C@@H:15]([OH:39])[C@@H:14]2[OH:40])(=O)=O)=CC=1.[CH3:41][N:42](Cl)[CH3:43].CCN(CC)CC>CN(C=O)C.O>[Cl:37][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[C@:17]1([C@H:16]([OH:38])[C@@H:15]([OH:39])[C@H:14]([OH:40])[C@@H:13]([CH2:12][N:42]([CH3:43])[CH3:41])[O:18]1)[O:19][CH2:20]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@]3(OCc4cc(Cl)c(Cc5ccc(C(C)C)cc5)cc43)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Reactant: CN(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-iso-propylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (15 mg, 0.025 mmol) and dimethylamino hydrochloride (48 mg, 0.588 mmol) in DMF (1 mL), was added Et3N (67 mg, 0.662 mmol). After being stirred for 24 h at 80° C., the reaction mixture was diluted with H2O and extracted 3× with AcOEt. The combined organic layers were washed with brine prior to drying over Na2SO4. The volatiles were removed under reduced pressure. The resulting residue was purified by preparative HPLC to yield 6 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.41 (s, 1H), 7.24 (s, 1H), 7.13 (s, 4H), 5.18 (d, J=13.5 Hz, 1H), 5.13 (d, J=13.5 Hz, 1H), 4.17-4.02 (m, 3H), 3.76-3.75 (m, 2H), 3.46-3.18 (m, 3H), 2.90-2.81 (m, 1H), 2.76 (s, 6H), 1.22 (d, J=6.9 Hz, 6H); MS ESI (m/z) 462 (M+1)+, calc. 461.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1cc(I)c(Br)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Temperature: 20 °C
Yield: 70.7 %

Procedure:
To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (Ref. Cottet, F. and Schlosser, M. Tetrahedron 60, 11896-11874 (2004)) (2.0 g, 6.3 mmol), 4-chlorophenylboronic acid (1.1 g, 6.9 mmol) and K2CO3 (1.7 g, 12.6 mmol) in 1,2-dimethoxyethane (24 mL) and H2O (8.0 mL) was added Pd(PPh3)4 (0.727 g, 0.63 mmol) under argon at 20° C. The reaction mixture was refluxed for 15 h under argon, then allowed to cool to 20° C. The reaction was quenched by addition of H2O (30 mL) and extracted with EtOAc (50 mL×3). The combined organic was washed with saturated aqueous NaHCO3 (50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized in EtOH to afford 1.35 g of the title compound as a light beige solid as the first crop. The second crop of the title product (0.44 g) was also isolated by concentrating the mother liquid followed by recrystallization in EtOH. LC/MS (method B): retention time=2.03 min, [M+H]+=301.9.
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH:13]=[N:14][OH:15].C=C.C(N(CC)CC)C>CN(C)C=O>[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:13]2[CH2:4][CH2:3][O:15][N:14]=2)[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Agent: C=C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C1=NOCC1
Reaction time: 0.5 h

Procedure:
At 60° C., a small amount of N-chlorosuccinimide is added to a solution of 50 g (171 mmol) of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime in 200 ml of dimethylformamide. Once the reaction has started, a total of 23.3 g (171 mmol) of N-chlorosuccinimide are metered in at 40-50° C. The reaction mixture is stirred for another 30 minutes, until conversion is complete according to HPLC. The reaction mixture is then poured onto ice-water and the solid is filtered off with suction, washed three times with water and twice with n-pentane. The hydroxamic acid chloride is used moist and without further purification for the next reaction. The solid is dissolved in 250 ml of dichloromethane, and ethylene is passed through the solution. With continued introduction of ethylene, 20.3 q (200 mmol) of triethylamine are added dropwise. The reaction mixture is stirred at room temperature for about 72 hours, with repeated introduction of more gaseous ethylene.
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C.O>O1CCCC1>[C:19]([O:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])[CH3:20]
Reactant: OC(COc1ccccc1)COc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC(COc1ccccc1)COc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
9.6 g (39.3 mmol) of 2-hydroxy-1,3-diphenoxypropane are dissolved in 80 ml of tetrahydrofurane (THF) and cooled by an ice bath. To the solution are added dropwise 6.8 g (86.4 mmol) of acetyl chloride and 6.0 g (59.0 mmol) of triethylamine successively. The reaction mixture is stirred at room temperature overnight, poured into 50 ml of water, and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate and hexane (1:9) as eluent, yielding 5.1 g of 2-acetyloxy-1,3-diphenoxypropane as a colorless liquid.
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.O[C:26]1([C:42]2[C:51]([OH:52])=[CH:50][C:49]3[CH2:48][CH2:47][CH2:46][CH2:45][C:44]=3[CH:43]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]1=[O:41]>>[OH:52][C:51]1[C:42]([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]2=[O:41])=[CH:43][C:44]2[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=2[CH:50]=1
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCCC3)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: 1H NMR (300 MHz, CDCl3) δ 7.42-7.32 (m, 2H), 7.20 (t, 1H), 6.84 (d, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 5.12 (s, 1H), 4.47 (ABq, 2H), 4.21 (q, 2H), 2.76-2.44 (m, 4H), 1.78-1.64 (m, 4H), 1.24 (t, 3H); MS (ES+) m/z 366 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH3:16])[CH:13]=2)[N:8]=[C:7]([Cl:17])[N:6]=1)[CH:2]=[CH2:3].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[ClH:17].[CH2:18]([NH:21][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH3:16])[CH:13]=2)[N:8]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2ccc(NC)cc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2cc(NC)ccc2n1
Product: Cl

Procedure:
In a sealed tube were stirred 100 mg (0.40 mmol) of 4-allylamino-2-chloro-6-methylaminoquinazoline and 761 mg (13.33 mmol) of allylamine at 140° C. for 22 hours. A saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 100 mg (yield: 92.4%) of a free base compound of the title compound.