Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)#[N:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:26][CH:27]=1)#[N:2]
Reactant: COC(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Methyl 4-[5-(4-cyanophenoxy)-pentoxy]-3-methoxybenzoate (3600 g, 9.74 mol) is dissolved in tetrahydrofuran (36 L) with warming to 30° C. The solution is then cooled to 20° C. and a solution of tetrabutylammonium hydroxide (40% in water, 7.1 L, 1.64 m) is added over 20 minutes. The reaction mixture is then stirred at an internal temperature of 25° C. for 7 hours and overnight at room temperature (23° C.). After cooling to 10° C. with an ice bath, hydrochloric acid (1.0 N, 14.4 L) is added over 1 hour. After stirring and cooling to 10° C. for three hours, the product is filtered, washed with water (24 L) and dried in vacuo (76° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid, mp 159°-161° C. HPLC indicates 99.1% purity. A second crop of acid is obtained from the flitrates after diluting further with water (20 L). The product is filtered, washed with water (4×3 L) and dried in vacuo to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid, mp 158°-160° C., (HPLC indicates 98.3% purity).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH3:23][Sn](C)(C)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.CN(P(N(C)C)(N(C)C)=O)C>[CH3:23][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Temperature: 120 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), dichlorobis(triphenylphosphine)palladium(II) (50 mg, 0.07 mmol, 0.15 equiv) and tetramethyltin (270 μL, 1.91 mmol, 4.0 equiv) were combined in 5 mL of a 1:1 solution of DMF:HMPA. The solution was degassed and heated to 120° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H18N3O4S (M+H+): 324.1013. Found 324.1014.
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:45])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=3[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]2)[CH:12]=1>CN(C1C=CN=CC=1)C>[CH2:41]([C:15]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:22][C:21]=2[F:40])[C:17](=[O:18])[N:13]([C:11]2[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=2[Cl:45])[N:14]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 84 %

Procedure:
Propionyl bromide was reacted with 2(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) in the presence of DMAP according to the procedure of Example 69. Flash chromatography of the crude product on silica gel (gradient elution with 3:1 to 1:1 hexane-EtOAc) gave an 84% yield of the title compound as a white solid, mp 103°-105° C.; homogeneous by TLC (1:1 hexane-EtOAc); mass spectrum (FAB) m/e 648 (M+Li)+.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Reactant: NNc1ccccn1
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (68.2 g, 0.34 mol) and 2-hydrazinopyridine (37.1 g, 0.34 mol) in ethanol (500 mL) was heated under reflux for 1 hour. After the solution was cooled to room temperature, the resulting crude crystals were filtered. The crystals were washed with ethanol and air-dried to give the title compound (50.2 g, 51% yield).
Reaction SMILES: C1(C[O:8][C:9](=[O:57])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:26]=[C:25]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:13]([CH2:12][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:26]=[C:25]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:24]=1)[CH2:10][C:9]([OH:57])=[O:8])([OH:15])=[O:14]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 6.5 g of N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 1.5 g of 10% palladium on carbon in 200 ml of THF was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane. Filtration gave 4.73 g (94% yield, mp 91°-94°) of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=O.[C:19]1(=[O:38])[N:23]([CH2:24][CH2:25][O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[C:22](=[O:33])[C:21]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:20]12>C(O)C>[CH3:7][C:5]1[NH:31][C:29]([CH3:30])=[C:28]([C:27]([O:26][CH2:25][CH2:24][N:23]2[C:22](=[O:33])[C:21]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:20]3[C:19]2=[O:38])=[O:32])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: C/C(N)=C/C(=O)OCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 83.3 %

Procedure:
Prepared by a method analogous to that of Example 1(a) from 14.95 g (60 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid methyl ester and 16.46 g (60 mmol) of 3-amino-crotonic acid-(2-phthalimidoethyl)ester in ethanol. 25.25 g (83%) of yellow crystals melting at 181°-182° C. are obtained.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:1]([O:9][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(O)c1cccnc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)c1cccnc1
Temperature: 25 °C

Procedure:
A Suspension of nicotinic acid (5.00 g, 40.6 mmol) in N,N-dimethylformaide (40 ml) was treated with sodium methoxide (2.19 g, 40.6 mmol). The resulting solution was treated with p-nitrobenzylbromide (8.77 g, 40.6 mmol) and heated at 50°, After heating 16 hrs the reaction was allowed to cool to ambient temperature and diluted with ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution and filtered. The organic fraction was separated and washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to a solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:37][CH2:38][CH:39]([F:41])[F:40])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:41][CH:39]([F:40])[CH2:38][O:37][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:6])[C:3]2[C:7]([F:19])=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[C:2]=2[Cl:1])=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)O)c1Cl
Reactant: Nc1ccc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1Cl

Procedure:
Prepared analogously to 43b from 2-chloro-3-(tert-butylcarbonylamino-methyl)-6-fluoro-benzoic acid and 5-amino-N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)-benzamide with HATU and TEA in THF.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[CH:16]1([CH2:19][N:20]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38](=[O:49])(=[O:48])[N:39]([CH2:44][CH2:45][O:46][CH3:47])C(C)(C)C)=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][N:22]=[C:21]2[CH2:50][CH3:51])[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][N:20]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38](=[O:48])(=[O:49])[NH:39][CH2:44][CH2:45][O:46][CH3:47])=[CH:36][CH:37]=4)[N:26]=3)=[CH:23][N:22]=[C:21]2[CH2:50][CH3:51])[CH2:18][CH2:17]1
Reactant: CCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N(CCOC)C(C)(C)C)cc3)n2)n1CC1CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
Anisole (4.57 ml) followed by trifluoroacetic acid (22 ml) was added to 4-(1-cyclopropylmethyl-2-ethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(t-butyl)sulphamoyl]anilino}pyrimidine (Method 76; 3.7 g, 7.22 mmol). The mixture was stirred at ambient temperature for two hours, the volatiles were evaporated and the residue dissolved in water and then extracted with EtOAc. The aqueous layer was neutralised with saturated aqueous sodium hydrogen carbonate solution and extracted with EtOAc. The extract was dried and the solvent removed by evaporation. The residue was purified by chromatography on silica gel eluting with EtOAc/MeOH (100:0 increasing in polarity to 98:2) to give the title compound (1.58 g, 48%) as a foam. NMR: 0.00-0.02 m, 2H), 0.18-0.20 m, 2H), 0.86-0.90 (m, 1H), 1.10 (t, 3H), 2.60 (q, 2H), 2.75 (q, 2Hy, 3.01 (s, 3H>, 3.18 (q, 2H), 4.40 (d, 2H), 7.10 (d, 1H), 7.35 (t, 1H), 7.52 (s, 1H), 7.57 (d, 2H), 7.77 (d, 2H), 8.30 (d, 1H), 9.70 (s, 1H); m/z 457.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CCOC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OCC)C3)cc1

Procedure:
Compound dy was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with ethyl chloroformate. LC-MS: m/z=+469 (M+H)+.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4]1.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:17]([O:20][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCOC(=O)C[C@H]1C[C@@H](COC(C)=O)OC(C)(C)O1
Temperature: 27.5 °C

Procedure:
Mixture of ethyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (60 grams), tetra butyl ammonium bromide (79 grams) and anhydrous sodium acetate (61.2 grams) was heated to reflux temperature and stirred. After the completion of the reaction, the reaction mixture was cooled to 25-30° C. and petroleum ether (50 ml) was added to it then stirred for 60 minutes at 25-30° C. The reaction mixture was filtered and washed with petroleum ether. The solvent from the filtrate was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([Cl:6])([C:3](Cl)=O)=O.CN(C=O)C.[N:12]1[C:17]2[CH:18]=[CH:19][S:20]C=2C(=O)[NH:14][CH:13]=1>O>[Cl:6][C:1]1[C:3]2[S:20][CH:19]=[CH:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2ccsc12
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccsc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a stirred solution of (COCl)2 (7.33 mL, 84.11 mmol) in anhydrous (CH2Cl)2 (20 mL) at 0° C. under nitrogen was added DMF (4.47 mL, 57.18 mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19) (4 g, 26.28 mmol) in anhydrous (CH2Cl)2 (5 mL) was added drop wise to the reaction mixture which was stirred for 20 min at 0° C., warmed to room temperature over another 20 min, heated at 80° C. for 1.5 hours, and cooled to room temperature. Finally, the reaction mixture was poured into water and extracted with DCM. The extract was washed sequentially with water, brine, dried over Na2SO4, filtered and evaporated to afford the title compound 20 (4.36 g, 97% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.02 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 7.75 (d, J=5.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([CH:12]1[CH2:7][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:17]
Reactant: C=Cc1ccc(F)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 120.1 %

Procedure:
In an oven-dried two-neck round flask equipped with condenser and Argon inlet was charged with 40 mL of newly opened anhydrous chloroform. Dry Argon gas was bubbled through the chloroform. copper (I) iodide (38 mg, 1 mol %) and palladium (II) acetate (45 mg, 1 mol %) were added to the Chloroform and stirred at room temperature for 15 minutes under argon. Then 4-fluorostyrene (2.4 mL, 20 mmol) in 20 mL of dry chloroform was added to the above solution. Finally ethyl diazoacetate (8.3 mL, 80 mmol) in 10 mL of chloroform was added dropwise to the reaction mixture over 2 hour. The reaction mixture was heated at 80° C. for overnight. The reaction mixture was cooled down to room temperature and rotavaped to afford dark green oil. The residue was diluted with 200 mL of ethyl acetate and washed with saturated sodium bicarbonate aqueous solution (1×50 mL), water (1×50 mL) and brine (1×50 mL) respectively. The ethyl acetate layer was dried over Sodium sulfate and concentrated to give 5 gram of light brown oil as crude product, which was purified with flash chromatography (40 gram prepacked column by Isco, Inc., 230-400 mesh, eluants: 0-20% ethyl acetate in hexanes) to obtain 2.625 grams of the desired product as clear oil. The trans configuration of the structure was confirmed by NOE of 1H NMR, yield=62%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15]([OH:16])=[C:14]([OH:17])[N:13]=[C:12]([C:18]([NH:21][CH2:22][CH2:23][CH2:24]O)([CH3:20])[CH3:19])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]([CH3:20])([CH3:19])[NH:21][CH2:22][CH2:23][CH2:24][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(NCCCO)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)NCCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O

Procedure:
Crude N-(4-fluorobenzyl)-5,6-dihydroxy-2-{1-[(3-hydroxypropyl)amino]-1-methylethyl}pyrimidine-4-carboxamide prepared as described in Step 1 was dissolved in THF, and treated with triphenylphosphine (1.5 eq.) and DEAD (1.5 eq.). The mixture was stirred under nitrogen, after 14 hours additional reagents (2 eq.) were necessary to complete reaction. Solvent was evaporated under vacuo and the residue loaded on cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions and further purification of the residue by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) gave, after lyophilization, title compound as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[S:14][CH:15]=1.C([O:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:29][CH2:28][CH2:27][CH2:26][OH:25])[CH2:20][CH2:21]2)[S:14][CH:15]=1
Reactant: CC(=O)OCCCCBr
Reactant: c1cc2c(cc1-c1csc(C3CCNCC3)n1)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCCCN1CCC(c2nc(-c3ccc4c(c3)CCCC4)cs2)CC1

Procedure:
The preparation is carried out as described starting from 39 mg (0.13 mmol) of 4-[4-(5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine and 30 μl (0.20 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 2N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([N:11]([CH3:25])[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:16][CH:17]=1)[N:5]=2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:13]=1)[C:6]1[N:5]=[C:4]2[S:3][C:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])=[N:10][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)(methyl)amino]phenyl}-2,2,2-trifluoroacetamide (174 mg, 0.474 mmol) in pyridine (1.7 mL) was added cyclopropanecarbonyl chloride (55 μL, 0.610 mmol) at −20° C., and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (147 mg, 71%) as a pale-violet powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([CH:11]=[N:12]O)=[C:4]2[CH:3]=1.C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([C:11]#[N:12])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2C=NO)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2nn3ccc(Br)cc3c2C#N)cc1

Procedure:
A mixture of Example 19E (3.09 g, 8.93 mmol) in acetic anhydride (100 mL, 1060 mmol) was heated at 140° C. for 24 hours, cooled and concentrated. The residue was triturated with diethyl ether to give a brown solid that was collected by filtration and dried (2.33 g, 80%). MS (ESI+) m/z 328/330 (M+H)+.
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].Cl.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][C:16]2([CH2:23][O:22][CH:21]([CH2:24][CH2:25][CH2:26][NH2:27])[O:20][CH2:19]2)[CH2:15][O:14]1>>[C:2]([NH:1][C:4](=[NH:5])[NH:27][CH2:26][CH2:25][CH2:24][CH:21]1[O:20][CH2:19][C:16]2([CH2:17][O:18][CH:13]([CH2:12][CH2:11][CH2:10][NH:9][C:4]([NH:1][C:2]#[N:3])=[NH:5])[O:14][CH2:15]2)[CH2:23][O:22]1)#[N:3]
Reactant: N#C[N-]C#N
Reactant: NCCCC1OCC2(CO1)COC(CCCN)OC2
Agent: Cl
Agent: [Na+]
Product: N#CNC(=N)NCCCC1OCC2(CO1)COC(CCCNC(=N)NC#N)OC2

Procedure:
The reaction of sodium dicyanamide with 3,9-bis(3-aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane dihydrochloride proceeds as shown by the following formula (5) to produce 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane aimed at. ##STR12##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][NH:10][C:11]([C@@:13]2([CH3:27])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[C:33]1([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:18][C:15]1([CH3:19])[N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@@:13]([CH3:27])([C:11](=[O:12])[NH:10][CH2:9][C:8](=[O:28])[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:3]([C:29]([F:31])([F:32])[F:30])[CH:4]=2)[CH2:17][O:16]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(O)c(C(F)(F)F)c1
Reactant: OCCCCCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (114 mg, 0.25 mmol, 1.0 equiv) and 6-phenylhexan-1-ol (45 mg, 0.25 mmol, 1.0 equiv) in DCM (1 mL) was added polymer bond PPh3 (125 mg, 0.75 mmol, 3.0 equiv). The reaction mixture was stirred at rt for 0.5 hour and cooled to 0° C. A solution of DIAD (0.053 mL, 0.25 mmol, 1.0 equiv) in DCM (0.5 mL) was added drop wise to the reaction mixture. The reaction mixture was stirred at rt for 2 hours, filtered and evaporated under reduced pressure to give a residue, which was purified by SiO2 column chromatograph (30-50% EtOAc in hexanes) to give (R)-tert-butyl 2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate in 75% (155 mg) yield. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 3.31 min with gradient 50-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=621.6.