Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1cc(CI)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1cc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc(OC)c1OC

Procedure:
In analogy with Example 44c), 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and with the addition of 0.66 ml of DMPU and alkylated with 1.008 g 3,4,5-trimethoxybenzyl iodide. Chromatography on silica gel (eluent, hexane/acetone 3:1) affords the title compound. TLC Rf (hexane/acetone, 3:1)=0.22. FAB-MS M+ =485.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:22]=1[O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H](COc2ccc3ccccc3c2)C1
Yield: 86 %

Procedure:
The procedure is the same as for Example 1 (Stage 1.2) starting from 2.00 g (9.94 mmol) of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (commercial), 2.00 g (13.91 mmol) of naphth-2-ol, 3.90 g (14.91 mmol) of triphenylphosphine and 3.01 g (14.91 mmol) of diisopropyl azodicarboxylate. 2.80 g of product are obtained in the form of an oil after purification on a column of silica gel, elution being carried out with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=O)[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]3[CH:25]=[CH:26][N:27]=[C:15]23)=[C:4]([F:28])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[S:30])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]3[CH:25]=[CH:26][N:27]=[C:15]23)=[C:4]([F:28])[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Nc1cc(-n2c(=S)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl

Procedure:
A mixture of 8-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.6 g), diphosphorus pentasulfide (0.5 g) and toluene (30 ml) was heated to reflux for 3 hours. The solid matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography of silica gel (developing solvent: ethyl acetate) to give the compound of interest (0.5 g) as a yellow crystal.
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][OH:20]>C[O-].[Na+]>[OH:20][CH2:19][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:17][CH3:16])=[O:18]
Reactant: O=C1CCCCCCCCCCCCCCCO1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CCCCCCCCCCCCCCCO
Temperature: 60 °C
Yield: 90.2 %

Procedure:
76.3 gm of 16-hexadecanolide and 0.29 gm of 28% sodium methoxide solution were dissolved into 250 gm of methanol, and the solution was heated at 60° C. for 60 hours while stirring. The reaction mixture was cooled to deposit crystals. The crystals were collected by filtration, washed, and dried to obtain 77.5 gm of methyl 16-hydroxyhexadecanoate (yield: 90.2%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1/[CH:24]=[CH:25]\[C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:27]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9](/[CH:24]=[CH:25]\[C:26]3[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:31]=3)[CH2:10]2)(=[O:15])=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2)cc1
Yield: 95 %

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-[(Z)-2-(4-methoxycarbonylphenyl)vinyl]pyrrolidine (15.5 g) in 90% aqueous trifluoroacetic acid (100 ml) was stirred at room temperature for 30 minutes and the solvent was evaporated in vacuo. The residue was suspended in chloroform (200 ml) and the solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residual solid was collected by filtration to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-2-(4-methoxycarbonylphenyl)vinyl]pyrrolidine (11.9 g) as a white powder.
Reaction SMILES: C(OC(N1CCC2(CC(=O)C3C(=CC=C(Br)C=3)O2)CC1)=O)(C)(C)C.C(O[K])(C)=O.[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[C:40](Br)[CH:39]=[N:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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>[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1cncc(Br)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
tert-butyl-6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (19.8 g, 50.0 mmol), bis(pinacolato)diboran (14.0 g, 55.0 mmol), Pd(OAc)2 (560 mg, 2.50 mmol), DPPF (2.77 g, 5.00 mmol), and AcOK (5.82 g, 60.0 mmol) were suspended in dioxane (250 mL) and heated at 100° C. for 10 hours. After cooling down to room temperature, 5-bromo-nicotinic acid tert-butyl ester (14.2 g, 55.0 mmol), Pd(PPh3)4 (5.78 g, 5.00 mmol) and 2M Na2CO3 aq. (125 mL, 250 mmol) were added to the reaction mixture; and then heated at 100° C. for 15 hours. The reaction mixture was diluted with EtOAc and H2O, organic layer was washed with brine and dried over MgSO4. After filtration, the solvents were removed in vacuo and the residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 6/4) and the obtained brown solid was crystallized from EtOAc/hexane (1/1) to afford 5-{1′-tert-butoxycarbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])=[CH:22][CH:21]=1)#[CH:19]>C(N(CC)CC)C.O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([C:19]#[C:18][C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])=[CH:22][CH:21]=2)=[CH:3][CH:4]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#Cc1ccc(C(=O)OCCCCCCC)cc1
Reactant: CCCCCCCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCOC(=O)c1ccc(C#Cc2ccc(C(=O)OCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, heptyl 4-iodobenzoate (2a) (3.64 g, 10.5 mmol) was dissolved in anhydrous triethylamine (8.6 mL), and anhydrous tetrahydrofuran (4.0 mL), triphenylphosphine (39.3 mg, 0.150 mmol), copper (I) iodide (43.8 mg, 0.230 mmol), and Pd(PPh3)2Cl2 (27.9 mg, 0.0397 mmol) were added. Thereafter, a solution of heptyl 4-ethynylbenzoate (4a) (2.64 g, 10.8 mmol) in anhydrous tetrahydrofuran (2.0 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered through celite and, after removal under reduced pressure, diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:10). Subsequent recrystallization from methanol/ethanol (5:1, v/v) gave bis[4-(heptyloxycarbonyl)phenyl]acetylene (5a) (4.64 g, yield 95%) as a white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:24][CH3:25])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:28]>>[C:1]1([S:7]([C:10]2[C:11]([S:24][CH3:25])=[N:12][N:13]3[C:18]([Cl:28])=[CH:17][C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nn2c(O)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(Cl)cc(C(C)(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 1.34 g (3.5 mmol) of 3-benzenesulphonyl-5-tert-butyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of POCl3 was heated at reflux for 30 min. The reaction solution was cooled to RT and evaporated. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (silica gel, CH2Cl2/AcOEt 19:1) of the residue yielded 1.23 g (78%) g of 3-benzenesulphonyl-5-tert-butyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as a pale yellow foam.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[NH2:40][C@@H:41]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:42]([N:44]([CH2:56][CH:57]([O:61][CH2:62][CH3:63])[O:58][CH2:59][CH3:60])[CH2:45][C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([NH:40][C@@H:41]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[CH:67][CH:66]=2)[C:42]([N:44]([CH2:56][CH:57]([O:61][CH2:62][CH3:63])[O:58][CH2:59][CH3:60])[CH2:45][C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH:49]=[CH:48][CH:47]=2)=[O:43])=[O:17])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of 1-((3-benzylureido)methyl)cyclopropanecarboxylic acid (Compound VI-1) (182 mg, 0.77 mmol), hydroxybenzotriazol (126 mg, 0.51 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (98 mg, 0.51% mmol) in dichloromethane (1.5 ml) was added a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (125 mg, 0.25 mmol) and 4-dimethylaminopyridine (16 mg, 0.13 mmol) in dichloromethane (1.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetated (150 ml) and washed with saturated sodium bicarbonate (50 ml), water (10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Purif silica gel column chromatography (eluent: n-hexanae:ethylacetate=50:50 to 0:100) to obtain the title compound (175 mg, 97%).
Reaction SMILES: C[S:2]([CH3:4])=O.[CH2:5]([SH:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>Cl.II>[CH2:5]([S:17][S:2][CH2:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCS
Reactant: CS(C)=O
Agent: Cl
Agent: II
Product: CCCCCCCCCCCCSSCCCCCCCCCCCC
Temperature: 60 °C
Yield: 89.6 %

Procedure:
A mixture of 9 ml of DMSO (127 mmole), 12 ml of 1-dodecanethiol (50 mmole), 0.1 ml of 37 percent hydrochloric acid (1.2 mmole), and 10.8 mg of iodine (0.085 mmole as HI) was heated by a bath, while stirring magnetically, at about 60°C. After one and a fourth hours, the lower phase became amber colored. The mixture was cooled with stirring to produce fine crystals. These were filtered off and rinsed with DMSO. Recrystallization from acetone gave 9.02 g of didodecyl disulfide (90 percent of theory). Mp, 33°-5°C. (reported, 33°-4°C.).
Reaction SMILES: C(OC(=O)CN)C.C(O)(=O)CCCCCCC/C=C\CCCCCCCC.CCN=C=NCCCN(C)C.NCC(N)=O.[C:44]([N:63]([CH2:65][C:66]([OH:68])=[O:67])C)(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>CCO>[C:44]([NH:63][CH2:65][C:66]([OH:68])=[O:67])(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CN
Solvent: CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(=O)O

Procedure:
N-Oleoyl glycine (FIG. 7) was prepared by coupling glycine ethyl ester to oleic acid with EDCI (Cravatt et al. (1996) J. Am. Chem. Soc. 118, 580-590; Patterson et al. (1996) J. Am. Chem. Soc. 118, 5938-5945) followed by sequential transformation to the carboxylic acid (LiOH) and glycinamide (EDCI, NH4OH;). N-Oleoyl sarcosine was purchased (Pfaltz and Bauer) and converted to its ethyl ester by coupling with EtOH (DCC).
Reaction SMILES: [C:1]([O-])(=[O:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC=C/C=C/C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCC=C/C=C/CO
Yield: 87.4 %

Procedure:
To a solution of ethyl trans, trans-2,4-nonadienoate (25 g) in dry ether (250 ml) was added dropwise lithium aluminum hydride (5 g) with stirring under ice-cooling in the course of an hour. The reaction mixture was stirred for an hour at ambient temperature. To the resultant mixture was added ether containing water and then insoluble materials were removed by filtration. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oily trans, trans-2,4-nonadien-1-ol (20 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>CN(C=O)C.O.CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCCCCc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1ccc(CCCCCCCCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A suspension of 8-phenyloctyl chloride (10.1 g, 44.7 mmol), benzylamine (47.9 g, 44.7 mmol), and anhydrous powdered potassium carbonate in DMF (180 ml) refluxed overnight and cooled to RT. DMF was then evaporated under reduced pressure and water (300 ml) was added to the residue. The oil layer was separated, and the aqueous layer was further extracted with ether (2×150 ml). The ether extracts were evaporated and then combined with the oil layer. The combined oil was diluted with water (250 ml) and acidified with 10% HCl solution to give a white precipitate, 16 g, which was suspended in water (150 ml) and basified with ammonium hydroxide. After being stirred for 10 minutes, most of the white solid went into the solution. Ether (100 ml) was added and stirred for an additional 30 minutes. Organic layer was separated and the aqueous layer was extracted with ether (150 ml×2). Ether extracts were combined, washed with water and saturated brine solution, and dried (MgSO4), thus giving a light yellow oil of 11.90 g (90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1)#[CH:11].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[C:10][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH3:19])=[N:16][CH:17]=1
Reactant: Cc1nccc(Cl)c1I
Reactant: C#Cc1ccc(NC)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1ccc(C#Cc2c(Cl)ccnc2C)cn1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 20 mg (0.08 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 11 mg (0.09 mmol) (5-Ethynyl-pyridin-2-yl)-methyl-amine using 1.5 mg (0.01 mmol) CuI, 5.5 mg (0.01 mmol) PdCl2(PPh3)2 and 0.11 mL (0.8 mmol) triethylamine in 1 mL dry DMF. After completion of the reaction the product is purified by RP-HPLC using a ACN/H2O gradient (95:5 to 70:30). Yield: 20 mg (98%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][OH:46])[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:51]([O:53][CH:54]([CH2:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH3:52]>C1COCC1.O>[CH:32]1[C:42]2[C:41](=[CH:43][CH2:44][CH2:45][O:46][C:64]3[CH:63]=[CH:62][C:61]([CH2:60][CH:54]([O:53][CH2:51][CH3:52])[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:66][CH:65]=3)[C:40]3[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=3[CH2:38][O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: OCCC=C1c2ccccc2COc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCC=C2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 3-(6H-dibenzo[b,e]oxepin-11-ylidene)-1-propanol (0.252 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 18 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to an orange gum. This was then purified by column chromatography on silica gel (20% Et2O in petroleum eluent) to give the title compound as an inseparable 4:1 mixture of E and Z double-bond isomers, as a pale yellow gum; 0.252 g (53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])=[CH:28][CH:27]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
A solution of 8.3 g (44.4 mmol) of 5-chloro-2-methoxybenzoic acid and 7.8 g (48.1 mmol) of carbonylbisimidazole in 200 ml of absolute THF was stirred at room temperature for 2 h. 7.7 ml (50.0 mmol) of 2-(4-bromophenyl)ethylamine and 10 ml of triethylamine were added and the resulting solution was stirred at room temperature for 24 h. The reaction solution was then poured onto water, and the deposited precipitate was filtered off with suction and washed with water. Drying of the precipitate yielded 15.8 g of the title compound in the form of a slightly yellow-colored solid. M.p.: 104-109° C. Rf (silica gel, EA/heptane 2:1)=0.66. MS (ESI): m/z=368/370 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:24])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(Br)ccc12
Temperature: 115 °C
Reaction time: 3 h

Procedure:
20.4 ml (0.12 mol) of N-ethyldiisopropylamine were slowly added to a suspension of 55.0 g (0.24 mol) of 7-bromo-3H-quinazolin-4-one in 300 ml of phosphorus oxytrichloride. The reaction mixture was stirred at 115° C. for 3 h and subsequently allowed to come to room temperature. Conventional work-up gave 48.0 g of 7-bromo-4-chloroquinazoline; HPLC/MS (M+H)+=244 as solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.N1C=C[CH:16]=[CH:15][C:14]=1[CH:19]=[O:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:16]/[CH:15]=[CH:14]/[CH:19]=[O:20])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=Cc1ccccn1
Product: O=C/C=C/C=Cc1cnc2ccccc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 3-quinolinecarboxaldehyde for the 2-pyridinecarboxaldehyde of Reference Example 5. MS 210 (M+H)+.