Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C1C=CC=CC=1>[CH:29]1([C:33]([N:19]2[CH2:18][CH2:17][C@@:14]34[C:15]5[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(O)CCC(=O)C3
Reactant: O=C(Cl)C1CCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@]1(O)CCC(=O)C3

Procedure:
In an anhydrous system 32 g of 3-methoxy-14-hydroxy-6-ketomorphinan, 16 ml triethylamine and 300 ml of benzene are stirred together and, over a 30 minute period, a solution of 13 g of cyclobutylcarbonylchloride in 100 ml of benzene is added. The internal temperature is kept below 25° by means of an ice bath, after which stirring is continued for four more hours at room temperature. In the isolation, triethylaminehydrochloride is removed by filtration, the solvent evaporated, and the residue solidified by stirring in 200 ml of petroleum ether to give crude N-cyclobutylcarbonyl-3-methoxy-14-hydroxy-6-ketomorphinan.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][O:12][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccccc1CBr
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccccc1OCc1cccc(Oc2ccccc2)c1
Reaction time: 6 h

Procedure:
To a solution of 3-phenoxybenzylalcohol (545 mg; 2.72 mmol) in DMF (5 ml) was added NaH (92 mg; 3.1 mmol; 80% dispersion in oil) and ethyl(E)-3-(2-(bromomethyl)phenyl)-2-propenoate (810 mg; 3.0 mmol). After 6 h at r.t., 20 mg extra NaH was added. The final mixture was stirred at r.t. for 10 h then quenched using 0.3 ml of AcOH. The mixture was diluted with Et2O (25 ml), washed with water (3×20 ml) and brine, dried over MgSO4 and concentrated. Flash chromatography with EtOAc:toluene 5:95 afforded the desired material.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of 76A (380 mg, 1.01 mmol) in THF (5 mL) at −78° C., was added NaHMDS (1.3 mL, 1.0M, 1.3 mmol), dropwise. The solution was stirred at −78° C. for 3 h. A solution of MeI (0.62 mL, 10 mmol) in 2 mL THF was added. The solution was stirred −78° C. for 3 h, and −40° C. for 1 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 76B (70 mg, 18%). MS (ESI) m/z 388.3 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:24]=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:24]([NH:23][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:25])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1C=CC(NC(=O)Nc3ccccc3)C1)c1cccc(Cl)c21
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a stirred solution of 5-(4amino-cyclopent-2-enyl)9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (50 mg, 0.16 mmol) in CH2Cl2 (2 mL) was added isocyanatobenzene (0.018 mL, 0.18 mmol) and DMAP (catalytic amount) and stirred at r.t for 2 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the tide compound (35 mg, 50%). Mass Spectrum (M) (m/z) 433.3 (M−1). Anal. Calc. For C23H19ClN4O3; Theoretical: C, 63.52, H, 4.40, N, 12.88%; Found: C, 63.82, H, 4.45, N, 12.49%.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+:7].[C:8](=[O:10])=[O:9]>O>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+:7].[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:8](=[O:3])([O-:10])[O-:9].[Na+:7].[Na+:7]
Reactant: O=C=O
Agent: CC(O)C(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(O)C(=O)O
Product: O=C([O-])[O-]

Procedure:
A 10% sodium lactate solution was reacted at 30° C. according to the invention with a saturated solution of CO2 in water (carbonic acid). 46 g Sodium lactate produced 36 g of lactic acid and 20 g of sodium carbonate which may be used as a solution for neutralizing and regulating the pH of a fermentation. A further purification of the lactic acid can be performed by known methods using ion exchangers, esterification or extraction.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(F)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(F)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 20-3 (720 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (523 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][N:13]([CH:15]=O)[CH3:14].COC(OC)N(C)C.S([O-])(O)(=O)=O.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](/[N:11]=[CH:12]/[N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1ccccc1Br
Agent: COC(OC)N(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1Br

Procedure:
The starting material, 2-bromobenzene-1-sulfonamide, is commercially available. Reaction of 2-bromobenzene-1-sulfonamide in a solvent such as DMF, with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by the addition of sodium hydrogen sulfate in water, yields 2-bromo-N-[1-dimethylaminometh-(E)-ylidene]benzene-sulfonamide. This compound is reacted with 4-methylphenylboronic acid to yield 4′-methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide, then the —(CH2)r-L moiety is added, for example, by a halogenation reaction, to form compound (1c).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>O1CCCC1.CCOC(C)=O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(OCCCl)cccc21
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-(2-chloroethoxy)-1H-indole (3.4 g, 17.4 mmol) in tetrahydrofuran is treated with sodium hydride (60% in mineral oil, 1.04 g, 26.1 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzenesulfonyl chloride (3.4 mL, 26.1 mmol) stirred at room temperature overnight and treated with saturated NaHCO3 and EtOAc. The resultant phases are separated. The aqueous phase is extracted with EtOAc and the combined organic phase is washed sequentially with H2O and saturated NaCl, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography (silica gel, EtOAc/hexane: 2/8) to give the title compound as an off-white solid, 4.94 g (86%), mp 85-87° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C1(CN(CC2CC2)[C:6]2[N:11]=[C:10]3[N:12]([CH3:16])[C:13]([CH3:15])=[N:14][C:9]3=C[C:7]=2C=O)CC1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN.C(O)(=[O:41])C.[BH3-]C#N.[Na+]>CO>[CH3:15][C:13]1[N:12]([CH3:16])[C:10]([NH:11][C:6](=[O:41])[CH3:7])=[CH:9][N:14]=1
Reactant: CC(=O)O
Reactant: Cc1nc2cc(C=O)c(N(CC3CC3)CC3CC3)nc2n1C
Agent: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1cnc(C)n1C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde (0.220 g, 0.73 mmol.) and 3,5-bis-trifluoromethyl-benzylamine (215 mg, 0.87 mmol) in methanol (8 mL) was added acetic acid (0.042 mL, 0.073 mol) at 0° C. and the resulting reaction mixture was stirred for 15 min at the same temperature. NaCNBH3 (0.069 g, 0.011 mmol.) was added and the mixture was stirred at room temperature for 45 min. Methanol was removed under reduced pressure and the crude was extracted with ethyl acetate (250 mL) and washed with water (250 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 gof colorless gummy compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12][C:13]1[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][CH:14]=1>>[Br:12][C:13]1[N:18]=[C:17]([CH2:19][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=Cc1cccc(Br)n1
Product: CCOC(=O)C1CCCCN1Cc1cccc(Br)n1

Procedure:
13] Ethyl (2-piperidyl)carboxylate (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give ethyl 1-[(6-bromopyridin-2-yl)methyl]-piperidine-2-carboxylate as a colorless oil). MS m/z: 327.1 (M+H). Calc'd for C14H1gBrN2O2—327.22.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:5]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1CNCC(C)N1
Product: CC1CN(c2ccc(C#N)cn2)CC(C)N1

Procedure:
This compound was synthesized from 2,6-dimethyl-piperazine and 6-chloronicotinonitrile as described for example 39 step 1 (90 mg, crude) and it was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.0 Hz, 1H), 7.60 (dd, J=9.0 Hz, J=2.3 Hz, 1H), 6.60 (d, J=9.3 Hz, 1H), 4.27 (d, J=12.8 Hz, 2H), 2.96-2.88 (m, 2H), 2.52 (dd, J=12.4 Hz, J=10.9 Hz, 2H), 1.16 (d, J=6.3 Hz, 6H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:2]=1.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24].N>CCO.CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[NH:24])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:2]=1
Reactant: Nc1ccc2c(ccn2-c2cccnc2)c1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: N=C(Nc1ccc2c(ccn2-c2cccnc2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of compound 73 (275 mg, 1.32 mmol) in 15 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (750 mg, 2.63 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then it was diluted with CH2Cl2 (50 mL) and treated with saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were dried over sodium sulfate and concentrated to give a yellow solid which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to 5% 2M NH3 in MeOH/CH2Cl2 to give an off-white residue, compound 74 (210 mg, 50%). HPLC analysis indicated that the product is >98% pure. 1H NMR (DMSO-d6) δ 8.85 (d, J=2.5 Hz, 1H), 8.58 (d, J=4.0 Hz, 1H), 8.08-8.05 (m, 1H), 7.75-7.53 (m, 5H), 7.12-7.09 (m, 2H), 6.78 (dd, J=1.5, 7.0 Hz, 1H), 6.67 (d, J=3.1 Hz, 1H), 6.35 (brs, 2H); ESI-MS (m/z, %): 319 (M+1, 100%); ESI-HRMS calculated for C18H15N4S (MH+): 319.1011, observed: 319.1015.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=3)[C:12]=2[C:13]([OH:15])=[O:14])[N:3]=1.[H-].[Na+].ClC[CH2:35][C:36]([CH3:41])([CH3:40])[C:37]([O-:39])=[O:38].[CH2:42](O)C.CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=3)[C:12]=2[C:13]([O:15][CH2:42][O:39][C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[O:14])[N:3]=1
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCOC(=O)C(C)(C)C)n1

Procedure:
0.9 g of (2.1 mmol) of 2-(4-chloro-6-methoxypyrimidin -2-yl)oxy-6-(4,6-dimethoxypyrimidin-2-yl) oxybenzoic acid, 0.1 g of 60% sodium hydride and 0.39 g (2.5 mmol) of chloromethylpivalate were reacted in N,N-dimethylformamide, treated and purified in the same manner as in Example 1. To the residue thus obtained, were added ethanol/hexane to precipitate a solid, which was filtered out to obtain 0.6 g of a white crystal having a melting point of from 83° to 85° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[CH2:15](I)[CH3:16]>>[CH2:15]([N:11]1[CH:12]=[CH:13][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)=[N:10]1)[CH3:16]
Reactant: CCI
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Product: CCn1ccc(B2OC(C)(C)C(C)(C)O2)n1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 85A, Step 1 starting from 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and ethyl iodide. LCMS (M+H−82)+: m/z=141.1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[N:32]=2)[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][N:34]=[C:33]([CH3:36])[N:32]=5)[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1noc(-c2cccc(I)c2)n1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nc(C)no4)c3)CCC(=O)CC2)cc1OC1CCCC1
Reaction time: 15 h
Yield: 78 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.200 g, 0.64 mmol) and 5-(3-iodophenyl)-3-methyl-[1,2,4]oxadiazole (0.201 g, 0.70 mmol) in dry triethylamine (4.6 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.032 g, 0.028 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and triphenylphosphine (a small crystal) at 70° C. for 1 h and at 25° C. for 15 h. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, was treated with cold dilute hydrochloric acid and was dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 5 to 10% ethyl acetate in methylene chloride/hexanes 1:1) and the pure fractions were combined, concentrated in vacuo, crystallized from ethyl ether and dried at 60° C. in vacuo to afford the titled compound as an off-white powder (0.235 g, 78%), mp 88°-91° C. Anal. (C29H30N2O4) calcd: C 74.02, H 6.43, N 5.95, found: C 73.77, H 6.53, N 5.78.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.C(OC(C1(NC(C2CC(OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)CN2C(=O)NC([C:82](=[O:94])[NH:83][CH:84]2[C:92]3[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=3)C[CH:85]2[OH:93])C(C)(C)C)=O)CC1C=C)=O)C.C1([C@H](CO)N)C=CC=CC=1.OC1CC2C(=CC=CC=2)C1NC(C(N1CC(OC2C3C(=CC(OC)=CC=3)C=C(C3C=CC=CC=3)C=2)CC1C1(C(O)=O)CC1C=C)C(C)(C)C)=O>>[OH:93][CH2:85][C@H:84]([NH:83][C:82]([N:15]1[CH2:16][C@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:21]=2)[CH2:18][C@H:14]1[C:12]([NH:11][C@:6]1([C:4]([OH:3])=[O:5])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:13])=[O:94])[C:92]1[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: C=CC1CC1(C(=O)O)C1CC(Oc2cc(-c3ccccc3)cc3cc(OC)ccc23)CN1C(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: N[C@@H](CO)c1ccccc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](CO)c1ccccc1)C(=O)O

Procedure:
Compound 12 was treated as described for the preparation of 13 but with the use of (R)-2-phenylglycinol instead of 2-amino-N-(2-hydroxyindan-1-yl)-3,3-dimethyl butyramide instead of 2-amino-N-(2-hydroxy-indan-1-yl)-3,3-dimethyl-butyramide followed by ester hydrolysis as described for the preparation of compound 14 which gave the title compound. Purity by HPLC>95%. M+H+637.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:16]1([NH:19][C:20]([C:22]2[S:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:26]=2)=[O:21])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[N:11]=[C:10]([C:24]3[S:23][C:22]([C:20](=[O:21])[NH:19][CH:16]4[CH2:18][CH2:17]4)=[CH:26][CH:25]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCOc1nc(N)nc2ccc(Cl)nc12
Reactant: CC1(C)OB(c2ccc(C(=O)NC3CC3)s2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCOc1nc(N)nc2ccc(-c3ccc(C(=O)NC4CC4)s3)nc12
Temperature: 90 °C
Yield: 80.9 %

Procedure:
To a solution of 2-amino-4-ethoxy-6-chloropyrido[3,2-d]pyrimidine (50 mg) in 1,4-dioxane (7 ml) and water (2.5 ml) was added N-(cyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarboxamide (72 mg), K2CO3 (77 mg) and tetrakis(triphenylphosphine)palladium(0) (13 mg). The reaction mixture was heated to 90° C. for 1 hour. The reaction mixture was extracted with dichloromethane after which the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography, the mobile phase being a 3:97 MeOH/CH2Cl2 mixture, resulting in the pure title compound as a white powder (64 mg, yield: 81%) which was characterized by its mass spectrum as follows: MS (m/z): 356 ([M+H]+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and methyl 4-(bromomethyl)benzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, methyl 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (95%) as a colorless solid: mp 136-140° C.; 1H NMR (300 MHz, CDCl3) δ8.01 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.17 (d, J=7.4 Hz, 2H), 7.02 (dd, J=7.4, 7.4 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.54 (t, J=8.6 Hz, 2H), 3.89 (s, 3H), 3.06-2.92 (m, 2H); MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17](O)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)[Br:49]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@@H:17]([Br:49])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: BrC(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Br)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A mixture of salvinorin B (8a) (0.15 g, 0.38 mmol), triphenylphosphine (0.21 g, 0.80 mmol), and bromoform (0.15 g, 0.45 mmol) in CH2Cl2 (30 mL) was stirred at room temperature overnight. TLC indicated that starting material was still present after 16 h, thus additional triphenylphosphine (0.11 g, 0.42 mmol) and bromoform (0.07 g, 0.21 mmol) were added and the mixture was stirred for an additional 3 h. The solvent was removed under reduced pressure affording a crude solid. The oil was purified by column chromatography (eluent: 30% EtOAc/n-hexanes) to afford 0.10 g (59%) of 36 as a white solid, mp 170-173° C. (EtOAc/n-hexanes); 1H NMR (CDCl3): δ 1.15 (3H, s); 1.48 (3H, s); 1.60 (3H, m); 1.81 (1H, dd, J=2.7, 9.9); 1.95 (1H, dd, J=13.2, 26.1); 2.1 (2H, m); 2.27 (1H, s); 2.47 (1H, dd, J=4.8, 13.2); 2.66 (1H, m); 2.80 (1H, dd, J=3.3, 13.2); 3.70 (3H, s); 3.89 (2H, d, J=2.4); 4.45 (1H, m); 5.55 (1H, dd, J=4.8, 11.7); 6.38 (1H, dd, J=0.9, 1.5); 7.4 (2H, m).