Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][NH:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[OH:24][CH2:23][CH2:22][N:21]([CH3:20])[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4]
Reactant: CNCCO
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(CCO)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 15.5 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 2-(methylamino)ethanol (0.045 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided N2-(2-hydroxyethyl)-N2-methyl-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylglycinamide (0.022 g) as its trifluroacetic acid salt after reverse-phase HPLC purification. MS (ESI) m/z 317 ([M+H]+); MS (ESI) m/z 315 ([M−H]−).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>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]>[CH2:1]([S:8][C:9]1[C:10]([Cl:17])=[C:11]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)c(Cl)c(SCc2ccccc2)c1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Fc1cc(SCc2ccccc2)c(Cl)c(N2CCCC2)c1

Procedure:
Intermediate 35 (1 g, 3.02 mmol), pyrrolidine (0,257 g, 3.62 mmol), Pd2dba3 (55 mg, 0.06 mmol, 2 mol-%), BINAP (75 mg, 0.12 mmol, 4 mol-%) and NaOtBu (376 mg, 3.92 mmol) were suspended in 25 ml of dry, degassed toluene and refluxed for 2 h under argon atmosphere. After full conversion the reaction mixture was chilled and purified by extraction with 30 ml H2O and ethyl acetate. The organic layer was dried with MgSO4 and evaporated to form an oil. The product was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:18])[C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cnc(-c2ccc(F)cc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(-c2ccc(F)cc2)nc1Cl

Procedure:
A mixture of 2-(4'-fluorophenyl)-5-methyl-4-pyrimidinone (0.79 g, 3.9 mmol) (from example 5) and phosphorous oxychloride (3 ml) is heated to reflux for 1 hour.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][O:13][C:12]3=[O:22])=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[N:38](COCC[Si](C)(C)C)[CH:39]=[CH:40][N:41]=3)=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.FC(F)(F)C(O)=O>O1CCOCC1.ClCCl.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]>[NH:38]1[CH:39]=[CH:40][N:41]=[C:37]1[C:34]1[CH:35]=[CH:36][C:31]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@@H:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH2:14][O:13][C:12]4=[O:22])=[N:7][C:6]=23)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(-c3nccn3COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(-c3ccc(-c4ncc[nH]4)cc3)c2n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution containing (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (0.100 g, 0.278 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.334 g, 0.835 mmol) and 2M Na2CO3 (0.418 mL, 0.835 mmol) in dioxane (10 mL) was degassed with argon. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.3 mg, 0.0278 mmol) and Pd2(dba)3 (6.5 mg, 0.028 mmol), were added and the solution was degassed again with argon. The reaction vessel was sealed and heated to 80° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the crude material by column chromatography, eluting with 1-5% MeOH/dichloromethane afforded the protected intermediate which was taken up in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added and the mixture stirred at ambient temperature for 12 hours. The reaction mixture was concentrated, washed with saturated aqueous NaHCO3, extracted into ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 2-4% MeOH/dichloromethane, afforded (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one as a light yellow solid, 14 mg (12%). LCMS (APCI+) m/z 423 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=7.8 Hz, 1H), 8.65 (s, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.44-7.50 (m, 5H), 7.22 (s, 2H), 5.94-5.98 (m, 1H), 4.93 (t, J=8.6 Hz, 1H), 4.23-4.27 (m, 1H).
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.C(ON=O)(C)(C)C.[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1N.Cl>CS(C)=O>[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1[C:4]#[N:5]
Reactant: Nc1ccc(Br)cc1Br
Reactant: N#C[Cu]C#N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: N#Cc1ccc(Br)cc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Copper cyanide (2.32 g, 25.9 mmol) is added to stirred anhydrous dimethylsulfoxide (50 mL) at 60° C. to form a clear solution, followed by the addition of tert-butylnitrite (7.1 mL, 59.7 mmol) all at once. A solution of 2,4-dibromoaniline 21 (5.0 g, 19.9 mmol) in anhydrous dimethylsulfoxide (30 mL) is added dropwise, via cannula, to the mixture. After the addition is complete, the reaction mixture is allowed to stir for 1 hr. After being cooled to 45° C., the mixture is slowly treated with 5N hydrochloric acid (50 mL). Five minutes later, the reaction mixture is cooled to ambient temperature before being extracted with ethyl acetate/hexane (1:1; 2×300 mL). The combined organic layers are washed with water (100 mL) and brine (100 mL), dried, concentrated in vacuo, and then chromatographed on silica (0–5% ethyl acetate in hexane) to give the title compound (1.61 g, 31% yield). FD(+)MS m/z 259, (M+) consistent with 2 Br.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:75]=[CH:74][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH:46]=[C:47]([C:51]([C:53]4[N:54]=[CH:55][N:56]5[CH:60]=[C:59]([Sn](CCCC)(CCCC)CCCC)[S:58][C:57]=45)=[O:52])[CH:48]=[N:49][CH:50]=3)[CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:59]3[S:58][C:57]4=[C:53]([C:51]([C:47]5[CH:48]=[N:49][CH:50]=[C:45]([CH2:44][N:41]6[CH2:42][CH2:43][N:38]([C:36]([O:35][CH2:34][C:33]7[CH:74]=[CH:75][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=7)=[O:37])[CH2:39][CH2:40]6)[CH:46]=5)=[O:52])[N:54]=[CH:55][N:56]4[CH:60]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(CN4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(CN6CCN(C(=O)OCc7ccc([N+](=O)[O-])cc7)CC6)c5)c4s3)[C@H](C)[C@H]12
Yield: 21.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methylpyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (172 mg) was prepared in the same manner as in step a) of Example 1, except that 337 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 780 mg of 7-[5-[4-(4-nitrobenzyloxycarbonyl)-piperazin-1-yl]methylpyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccc3ccccc3c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-2′-acetonaphthone. tlc: Rf=0.8 (50% ethyl acetate in hexanes)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1>>[C:28]1([CH3:32])[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:15][C@@H:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][C@@H:11]4[CH2:13]3)[CH:17]=[N:18][CH:19]=2)=[O:22])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NC(=O)c2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)c2)c1

Procedure:
The product from Example 33B and m-toluidine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 423 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][CH:20]2[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21]2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: Oc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COc2cccc(Cl)n2)O1
Temperature: 85 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxypyridine (0.58 g, 4.50 mmol) and 2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (1.29 g, 4.50 mmol) in DMF (10 mL) was added cesium carbonate (2.97 g, 9.00 mmol). The reaction mixture was stirred at 85° C. for 18 h, and then partitioned between EtOAc (50 mL) and water (50 mL). The organic fraction was separated, washed with water (2×50 mL), then brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (1.03 g, 94%) as an off-white solid that was used without further purification. δH (DMSO-d6) 7.78 (1H, dd, J 8.1 and 7.5 Hz), 7.11 (1H, dd, J 7.5 and 0.6 Hz), 6.86 (1H, dd, J 8.1 and 0.6 Hz), 4.45-4.35 (1H, m), 4.33-4.18 (2H, m), 4.11-4.01 (1H, m), 3.77 (1H, dd, J 8.5 and 6.2 Hz), 1.34 (3H, s), 1.29 (3H, s). LCMS (ES+) 244.1 (M+H)+, RT 3.63 minutes (Method 1).
Reaction SMILES: O.Cl.Cl.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]3[O:25][C:24]4[CH:26]=[C:27]([O:30]C)[CH:28]=[CH:29][C:23]=4[O:22][CH2:21]3)[CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>Br>[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]3[O:25][C:24]4[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:23]=4[O:22][CH2:21]3)[CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)OC(CNCCCOc1ccc3cccnc3c1)CO2
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Oc1ccc2c(c1)OC(CNCCCOc1ccc3cccnc3c1)CO2
Temperature: 0 °C
Yield: 68.2 %

Procedure:
N-[3-(Quinolin-7-yloxy)propyl]-2,3-dihydro-7-methoxy-1,4-benzodioxin-2-methanamine dihydrochloride monohydrate (0.94 g, 2.0 mmole), prepared above in Example 4, was dissolved in 10 ml of 48% HBr and refluxed for 24 hours under a nitrogen atmosphere. Upon cooling, the mixture was poured into 100 ml of saturated sodium bicarbonate solution to which 50 g of ice had been added. When the ice had melted, the mixture was extracted three times with 150 ml portions of 3:1 dichloromethane-isopropanol, the extracts dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 50 g of silica gel with 3% methanol/chloroform and the product-containing fractions were combined and concentrated in vacuum. The crude free base thus obtained was crystallized from 50 ml of ethanol with the addition of 3 ml of 4N isopropanolic HCl to give 0.5 g of the title compound as a yellow dihydrochloride monohydrate, m.p. 245°-246° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+].Br[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:41][C:38]1[CH:39]=[CH:40][C:35]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:36][CH:37]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(N2c3ccccc3Cc3ccccc32)cc1

Procedure:
9.0 g of acridan (49.6 mmol), 446 mg of Pd(OAc)2 (2 mmol), 321 mg of tri-t-butylphosphine, 7.16 g of sodium t-butoxide (74 mmol), and 9.6 g of 1-bromo-4-fluorobenzene (54 mmol) in 90 mL of dry toluene was stirred under argon at room temperature for 2 h. TLC showed the absence of starting material. The reaction mixture was filtered through a Büchner funnel and the solid washed with CH2Cl2. The filtrate was then concentrated in vacuo and the residue was taken up in CH2Cl2 and refiltered. The filtrate was concentrated to dryness and chromatographed on silica gel in 5% ethyl acetate in hexanes, changing to CH2Cl2. Fractions containing product were combined and concentrated to dryness to afford N-(4′-fluorophenyl)acridan.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](O)=[C:4]([O:10][C:11]2([CH2:14][OH:15])[CH2:13][CH2:12]2)[N:3]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:13]1([CH:11]2[O:10][C:4]3[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([Cl:8])[C:5]=3[O:15][CH2:14]2)[CH2:12][CH2:16]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCC1(Oc2nc(Cl)nc(Cl)c2O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2c(n1)OC(C1CC1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 2,4-dichloro-6-(1-hydroxymethyl-cyclopropoxy)-pyrimidin-5-ol (135 mg, 0.54 mmol) and triphenylphosphine (180 mg, 0.65 mmol) in THF (8 mL) was added DIAD (128 μL, 0.65 mmol) and the mixture stirred at RT for 30 minutes, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-25% ethyl acetate in cyclohexane) affording 7-Cyclopropyl-2,4-dichloro-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (90 mg, 72%). 1H NMR (400 MHz, CDCl3): δ 4.30 (2H, s), 1.36-1.29 (2H, m), 1.01-0.95 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (962 mg, 0.005 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (3.3 g, 0.026 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-phenoxy-but-2-enoic acid ethyl ester (1.5 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (650 mg, 36%) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:23](=[O:25])[CH3:24])=[CH:4][C:5]2[CH2:6][CH:7]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:8]3[CH:13]([C:14]=2[CH:15]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[BH4-].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[OH:25][CH:23]([C:3]1[C:2]([OH:1])=[CH:15][C:14]2[CH:13]3[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:7]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:6][C:5]=2[CH:4]=1)[CH3:24]
Reactant: CC(=O)c1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(O)c1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Yield: 103.4 %

Procedure:
Combine 1-[3-Hydroxy-9-(4-hydroxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthren-2-yl]-ethanone (0.013 g, 0.04 mmol) and NaBH4 (0.016 g, 0.42 mmol) in ethanol (1.5 ml) and heat at 60° C. for 30 minutes. Remove solvent in vacuo and take into ethyl acetate, water, and sodium bicarbonate solution solution. Separate organic layer and wash with water. Dry over anhydrous sodium sulfate and remove solvent in vacuo to yield the titled compound (0.014 g, 100%). 1H NMR (CD30D): 7.16 (d, J=7.9 Hz, 2H), 7.1 (s, 1H), 6.78 (d, J=8.4 Hz, 2H), 5.12 (m, 1H), 3.2 (m, 3H), 2.8 (dd, J=10.5 and 7.5 Hz, 1H), 2.5 (m, 1H), 2.34 (m, 1H), 2.05 (m, 1H), 1.8-1.6 (m, 2H), 1.48 (m, 3H), 1.4-0.8 (m, 4H). MS m/z 337 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([CH:24]2[CH2:28][S:27][CH:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:25]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:23])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([CH:24]3[CH2:28][S:27][CH:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:25]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:23])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)NCCc2ccc(O)cc2)CSC1c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(C(=O)NCCc2ccc(OCCCCc3ccccc3)cc2)CSC1c1cccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
A solution of 280 mg of 1-bromo-4-phenylbutane in 5 ml of N,N-dimethylformamide was added to a mixture of 540 mg of N-[2-(p-hydroxyphenyl)ethyl]-3-tert-butoxycarbonyl-2(3-pyridyl)thiazolidine-4-carboxamide, 180 mg of potassium carbonate and 10 ml of N,N-dimethylformamide at room temperature. The mixture was stirred at 80° C. for 3 days. After cooling, 20 ml of water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The organic layer was washed in sequence with water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent: hexane-ethyl acetate=1:3) gave 360 mg of N-[2-[p-(4-phenylbutoxy)phenyl]ethyl]-3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Trifluoroacetic acid (5 ml) was added to the compound obtained, and the mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 230 mg of N-[2-[p-(4-penylbutoxy)phenyl]ethyl]-2-(3-pyridyl)-thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 130 mg of N-[2-[p-(4-phenylbutoxy)phenyl]ethyl]-2-(3-pyridyl) thiazolidine-4-carboxamide dihydrochloride. Melting point 102° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20].[CH3:21][Si:22]([CH3:39])([CH3:38])[C:23]#[C:24][Sn](CCCC)(CCCC)CCCC>CN(C=O)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>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:24]#[C:23][Si:22]([CH3:39])([CH3:38])[CH3:21])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[Cl:20]
Reactant: COC(=O)c1nc(-c2ccc(I)cc2)c(C)c(N)c1Cl
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(C)c(N)c1Cl
Temperature: 90 °C
Yield: 21.1 %

Procedure:
A mixture of methyl 4-amino-3-chloro-6-(4-iodophenyl)-5-methylpicolinate (264 mg, 0.66 mmol), trimethyl((tributylstannyl)ethynyl)silane (280 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) in anhydrous DMF (1.3 mL) was heated at 90° C. for 16 h. The reaction was cooled, diluted water, and extracted with ethyl acetate (2×). The organic layers were dried over anhydrous magnesium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-100% ethyl acetate/hexanes) afforded the title compound as a brown solid (52 mg, 21%): mp 158-164° C.; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 4.83 (s, 2H), 3.96 (s, 3H), 2.14 (s, 3H), 0.26 (s, 9H); IR (neat film) 3325, 3227, 2955, 2157, 1729, 1629, 1246 cm−1; ESIMS m/z 372 ([M]+).