Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][N:15]1[CH2:19][C@H:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[NH:17][C:16]1=[O:30].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:23]([O:22][C:20]([C@H:18]1[CH2:19][N:15]([CH3:14])[C:16](=[O:30])[N:17]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: CN1C[C@H](C(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C[C@H](C(=O)OCc2ccccc2)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 100 °C
Yield: 46.5 %

Procedure:
To a solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.1 g, 0.4 mmol) dissolved in 1,4-Dioxane (5 mL), (R)-benzyl 1-methyl-2-oxoimidazolidine-4-carboxylate (25c) (0.093 g, 0.4 mmol) was added at room temperature followed by Cs2CO3 (0.260 g, 0.8 mmol) and Argon gas was purged for 30 min. To the reaction mixture Pd2(dba)3 (0.036 g, 0.04 mmol) and Xanthphos (0.034 g, 0.058 mmol) were added at room temperature. The resulting reaction mixture was then heated to 100° C. for 5 h. After completion (by TLC), the reaction mixture was filtered through celite bed. The celite bed was washed with EtOAc (2×5 mL), the filtrates were combined, dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude residue was purified by column chromatography to provide 25d (0.075 g, 46%) as a colourless syrup.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[O:21]1CCOCC1>>[Br:1][C:2]1[C:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:20]=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Br)c(O[Si](C)(C)C(C)(C)C)c2n1
Reactant: C1COCCO1
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)ccc2ccc(C=O)nc12
Temperature: 80 °C
Reaction time: 32 h
Yield: 89 %

Procedure:
A slurry of SeO2 (0.869 g, 7.83 mmol) and 1,4-dioxane (20 mL) was warmed to 80° C. and then the product from Step B (2.3 g, 6.53 mmol) was added as a 1,4-dioxane solution (20 mL). The mixture was stirred at 80° C. for 32 hours. The mixture was cooled to ambient temperature and filtered through GF/F filter paper and the residual solid was washed with CH2Cl2. The filtrate was concentrated and purified by passing through a silica gel plug, eluting with 50% CH2Cl2/hexane to provide 2.14 g (89%) of the product as a yellow/orange solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C@H:11]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][C@H:15]1[C:20](=[O:39])[NH:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:13])(=O)C.Cl>CO.CCOC(C)=O>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]([CH2:30][NH:31][C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[C:23]([CH2:22][NH:21][C:20]([C@@H:15]2[CH2:16][O:17][CH2:18][CH2:19][N:14]2[C:12](=[O:13])[C@H:11]([OH:10])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:39])[CH:28]=1
Reactant: CC(=O)O[C@@H](C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)[C@H](O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
K2CO3 (0.016 g, 0.11 mmol) was added to a solution of (R)-1-{(S)-3-[2-{(tert-Butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]morpholino}-3,3-dimethyl-1-oxo-butan-2-yl acetate (0.28 g, 0.51 mmol) in MeOH (3 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), acidified with 1N aqueous HCl (5 mL) and the extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel; eluent: 70% EtOAc/hexanes) to afford the title compound as a pale yellow oil (0.25 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])[CH3:17])=[N:12][N:13]=2)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[Al+3]>C(S)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([NH:14][C:15](=[O:28])[C:16]([CH3:17])([S:18]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)(=[O:20])=[O:19])[CH3:27])=[N:12][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nnc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)[nH]2)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: CCS
Product: CC(C)(C(=O)Nc1nnc(-c2ccc(O)cc2)[nH]1)S(=O)(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.3 %

Procedure:
To a solution of 118 mg (0.29 mmol) of N-[5-(4-Methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide in ethanethiol (5 mL) are added 750 mg (2.9 mmol) of aluminium tribromide. The reaction is stirred at room temperature for 20 h. The reaction is quenched by addition of 12M aqueous HCl solution (2 mL) and diluted with water (10 mL). The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residual solid is washed with DCM to afford 45 mg of N-[5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide. Yield: 38%, ES-MS: m/z 395 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH3:21])=[O:8].[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=2[CH3:21])=[O:8])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1c(C)c(C)c(C(=O)CCCCCBr)c(C)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)c2c(C)c(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 83 %

Procedure:
A mixture of 0.194 g (2.6 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone, 0.55 g (2.6 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.10 g (7.8 mmol) of potassium carbonate in 20 mL of acetone and 2 mL of DMF was stirred at reflux for 17 hours. After workup as in Example 16, the crude product was purified by chromatography on 100 g of silica gel. Elution with 10% ethyl acetate-hexane gave 1.05 g (83% yield) of 4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 486 (C28H28O7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:24]2[O:23][CH:27]=[CH:26][CH:25]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccco1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccco4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 48.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (55 mg) and commercially available 2-furancarboxylic acid (32 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (91 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 35 mg of the title compound (yield: 48%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:11]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:8]([C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH3:7])=[O:10])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CCOc1ccc(Oc2ccc(CN)cc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Oc2ccc(CNC(=O)c3sc(C)nc3C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a stirred mixture of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (156 mg, 0.993 mM) and chloroform (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimde (190 mg, 0.393 mM) at 0°-10° C., and the mixture was stirred for 30 min at the same temperature. To this was added a solution (10 ml) of 4-(4-ethoxyphenoxy)benzylamine (242 mg, 0.993 mM) in chloroform at 0°-10° C., and the mixture was stirred for 12 h at the room temperature. The mixture was poured into ice water, and the mixture was extracted with chloroform. The extract was washed with saturated ammonium chloride solution and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-[4-(4-ethoxyphenoxy)benzyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide (171 mg, 45%) as colorless crystals, m.p. 99°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([NH:1][C:2]1[CH:3]=[C:4]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(3-aminophenylamino)-1-phenyl-methylidene]-2-indolinone and acetic anhydride in glacial acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12].N[CH2:14][CH2:15][CH2:16]O.C(O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.[Sn](Cl)Cl>O1CCOCC1.O.O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[CH3:12])[N:9]=[CH:16][CH:15]=[CH:14]2
Reactant: NCCCO
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: Cl[Ru](Cl)Cl
Agent: Cl[Sn]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1cc2cccnc2cc1C
Temperature: 180 °C
Reaction time: 20 h
Yield: 15.4 %

Procedure:
1-methoxy-2-methyl-4-nitrobenzene (3A) (5 g, 30.0 mmol), 3-amino-1-propanol (0.57 mL, 7.5 mmol), isopropanol (3.43 mL, 4.5 mmol), ruthenium(III) chloride hydrate (156 mg, 0.75 mmol), triphenylphosphine (588 mg, 2.24 mmol), and tin(II) chloride dihydrate (1.69 g, 7.5 mmol) in dioxane/H2O (67 mL/7 mL) were placed in a stainless steel pressure vessel. After the system was flushed with argon, the mixture was stirred at 180° C. for 20 hours. The reaction mixture was filtered through a short silica gel column (ethyl acetate/chloroform mixture) to eliminate inorganic compounds and concentrated under reduced pressure. The organic layer was poured into saturated brine, extracted with chloroform, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residual oily material was separated by column chromatography to give the product 3B (200 mg, 15%). LCMS-ESI+ (m/z): 174.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)[C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[OH:24])=[CH:18][CH:17]=3)[C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1O
Reactant: CCOC(=O)c1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Temperature: 80 °C

Procedure:
To a mixture of 3-(4-bromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (100 mg, 0.25 mmol), 2-hydroxyphenylboronic acid (53 mg, 0.38 mmol), K3PO4 (169 mg, 0.63 mmol), P(o-tolyl)3 (7.7 mg, 2.5×10−5 mol), and Pd(OAc)2 (2.8 mg, 1.3×10−5 mol) was added THF (1.5 mL) and H2O (0.5 mL). The mixture was purged with nitrogen for 15 min., capped, and heated to 80° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC (0–70% CH3CN in NH4OAc aq.) to give the titled compound. MS (ESI) m/e 430 (M+Na)+, 408 (M+H)+; 406 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=7.12 Hz, 3H), 4.29 (q, J=7.01 Hz, 2H), 6.89 (td, J=7.46, 1.35 Hz, 1H), 6.96 (dd, J=8.14, 1.02 Hz, 1H), 6.99 (s, 1H), 7.17 (m, 1H), 7.30 (dd, J=7.46, 1.70 Hz, 1H), 7.46 (m, 2H), 7.54 (m, 2H), 9.56 (s, 1H), 12.21 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[C:18]([F:22])[CH:19]=[C:20]([F:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[C:18]([F:22])[CH:19]=1
Reactant: C#CCCn1nc2cc(F)cc(F)c2n1
Reactant: Brc1ccccn1
Product: Fc1cc(F)c2nn(CCC#Cc3ccccn3)nc2c1
Yield: 45.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.26 mmol) and 2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 31 mg (0.11 mmol, 46%) of 4,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[S:25][CH:26]=[C:27]([C:29]([OH:31])=[O:30])[N:28]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.S(Cl)(Cl)=O.[CH2:38](OC(C1N=C(N)SC=1)=O)[CH3:39]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:38]([O:30][C:29]([C:27]1[N:28]=[C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:32][CH3:33])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])[S:25][CH:26]=1)=[O:31])[CH3:39]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3nc(C(=O)O)cs3)cc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)n1

Procedure:
2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylic acid, MS (ISP): m/e=508.3 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using thionyl chloride in toluene and dimethylformamide for the formation of the acyl chloride, and 2-amino-thiazole-4-carboxylic acid ethyl ester was used for the coupling, yielding 2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.[CH3:66][C:67]1([C:85](O)=[O:86])[CH2:72][O:71]C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:69][CH2:68]1.S(=O)(=O)(O)O.O>C1COCC1>[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([O:55][C:68]([C:67]([CH2:85][OH:86])([CH2:72][OH:71])[CH3:66])=[O:69])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)COC(c2ccccc2)(c2ccccc2)OC1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Temperature: 2.5 °C
Reaction time: 24 h

Procedure:
(189 mg) of 31-trimethyl silyl-42-ester of rapamycin with 5-methyl-2,2-diphenyl-1,3-dioxane-5-carboxylic acid [IId10] was dissolved in 2.8 ml THF and cooled to 0-5° C. Into the reaction mass 0.52 ml 2N sulphuric acid was added and stirred at 25-30° C. for 24 hrs. Then 2 ml THF and 0.52 ml 2 N sulphuric acid was added and stirred at 25-30° C. for 76 hrs. It was then concentrated on rotavapour, residue was dissolved in 2 ml ethyl acetate, and 2-3 drop perchloric acid (HClO4) diluted with 1 ml water was added. The reaction mixture was stirred at 25-30° C. for 24 hrs and reaction mass was dumped into water, and extracted with ethyl acetate. The layers were separated and washed the organic layer with 10% sodium bicarbonate solution and then water. It was dried over sodium sulfate, concentrated on rotavapor to obtain yellow colored oily compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc12
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one (537 mg, 1.33 mmol) in DMF (10 mL) was added a pyrrolidine (758 mg, 10.66 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the solid separated was filtered and dried under vacuum. The solid was triturated with ether and dried to give the title compound as a white solid. Yield: 232 mg (44%). MP 231-232° C. 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 7.90 (dd, J=8.0 Hz, 1H), 7.806 (br s, 2H), 7.42 (t, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.04 (s, 3H), 3.95 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.65 (m, 4H), 2.40 (s, 6H), 1.84 (m, 4H). MS (ES) m/z: 394.15 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.O1CCOCC1.B([C:38]1[CH:39]=[C:40]([Cl:47])[CH:41]=[C:42]([CH:46]=1)[C:43]([OH:45])=[O:44])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl.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.O>[Cl:47][C:40]1[CH:41]=[C:42]([CH:46]=[C:38]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=3[CH:26]=2)[CH:39]=1)[C:43]([OH:45])=[O:44]
Reactant: O=C(O)c1cc(Cl)cc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(Cl)cc(C(=O)O)c3)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (3.55 g, 8.5 mmol), dioxane (50 mL), water (10 mL), Tetrakis(triphenylphosphine)palladium(0) (0.196 g, 0.170 mmol), 5-borono-3-chlorobenzoic acid (2.55 g, 12.75 mmol), and cesium carbonate (4.15 g, 12.75 mmol). The tube was sealed and heated in an oil bath overnight at 85° C. The reaction mixture was then cooled, diluted with 300 mL of cold 0.5M HCl and stirred for 30 minutes. The resulting solid was washed with 0.5 N HCl then with water and allowed to dry under vacuum giving a quantitative yield of 3-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid which was used without further purification. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. LCMS m/z 424.09 (M+H), Rf 2.658 min., 88% purity.