Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:22]1[O:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([O:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:16]=2[C:23]=1[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCNC4)c23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add 300 mg of palladium black to an argon-blanketed solution of 2600 mg (4.69 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]-pyrimidine in 25 ml of a 4.4% solution of formic acid in methanol and stir at room temperature for five hours. Then add another 300 mg of palladium black and 0.9 ml of formic acid and stir at room temperature for a further 16 hours. After filtering off the catalyst, wash the catalyst residue with methanol/water. Concentrate the filtrate under reduced pressure, stir the residue in acetonitrile, filter off and dry under reduced pressure. 1376 mg (68% of theory) of the desired product are obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N+:16]([O-])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+].O=P(Cl)(Cl)[Cl:25]>>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[Cl:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(ccc[n+]2[O-])c1
Agent: [NH4+]
Agent: [OH-]
Product: O=S(=O)(c1ccccc1)c1ccc2nccc(Cl)c2c1
Yield: 27 %

Procedure:
A solution of 6-benzenesulfonyl-quinoline 1-oxid (135 mg, 0.47 mmol) in POCl3 (4 mL) was heated at 90° C. for 2 h after which the solution was poured on ice, ammonium hydroxide was added and extraction with DCM. The organic phase was dried (NaSO4), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, ethyl acetate:petroleum ether, 1:1) to yield a white solid (39 mg, 27%). MS m/z: 305 [M+H+].
Reaction SMILES: [Si]([O:18][C:19]1[CH:52]=[CH:51][C:22]([O:23][CH2:24][C@@H:25]([OH:50])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:49]=[CH:48][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:50][C@H:25]([CH2:24][O:23][C:22]1[CH:51]=[CH:52][C:19]([OH:18])=[CH:20][CH:21]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:49]=[CH:48][C:33]([NH:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1
Reactant: CCCCCC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 71.4 %

Procedure:
1-{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]-amino}ethyl)anilino]-1-piperidinyl}-1-hexanone (0.13 g, 0.168 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.058 g, 0.120 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:1][C:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:16]=[CH:15][CH:14]=[C:9]([CH2:10][OH:11])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cccc(-n2ncc(N)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Nc1cnn(-c2cccc(CO)c2)n1
Reaction time: 1 h

Procedure:
A stirred mixture of methyl 3-(4-amino-1,2,3-triazol-2-yl)benzoate (0.312 g.), lithium aluminium hydride (0.10 g.) and ether (50 ml.) was kept at room temperature for 1 hour. The excess of lithium aluminium hydride was destroyed with aqueous NaOH and the mixture was filtered. The filtrate was evaporated to give unpurified 4-amino-2-(3-hydroxymethylphenyl)-1,2,3-triazole.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[C:26]([F:33])[CH:25]=1>CN(C)C=O.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([N:13]2[CH2:12][CH2:11][C:9]3([O:8][CH2:7][C:6](=[O:16])[N:5]([CH:2]4[CH2:4][CH2:3]4)[CH2:10]3)[CH2:15][CH2:14]2)[CH3:31])=[C:26]([F:33])[CH:25]=1
Reactant: CC(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.9 %

Procedure:
A solution of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (2.483 mmol) in N,N-dimethylformamide (10 mL) was treated with potassium carbonate (7.45 mmol) and 4-bromo-1-(1-bromoethyl)-2-fluorobenzene (2.483 mmol). The reaction was stirred at room temperature for three days. The solution was diluted with water (200 mL) and was extracted three times with ethyl acetate. The organic layers were combined, washed with brine (five times), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (1.01 g, 89%). MS(ES)+ m/e 411.0/412.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN(CCCCNC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound 4 (1.13 g) in methanol (4 mL), an aqueous 2N sodium hydroxide solution (4 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The obtained residue was added by 2N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated to obtain the title compound having the following physical properties.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]=2[C:22]2[CH:31]=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[C:29]3[CH:28]=[C:27]([N+:45]([O-])=O)[C:26](=[O:48])[NH:25][C:24]=3[N:23]=2)[CH2:3][CH2:2]1.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:45][C:27]1[C:26](=[O:48])[NH:25][C:24]2[N:23]=[C:22]([C:7]3[C:8]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:31]=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[C:29]=2[CH:28]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc([N+](=O)[O-])c(=O)[nH]c3n2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc(N)c(=O)[nH]c3n2)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a stirred mixture of tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-6-nitro-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.085 g, 0.129 mmol), iron powder (0.300 g), ethanol (4.5 mL) and water (0.5 mL) was added ammonium chloride (0.100 g). The mixture was stirred at 85° C. for 30 min. After cooled to room temperature, the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 3-(6-amino-2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.068 g, yield; 84%).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH:7]([CH3:15])[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)(=O)=O.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CCO>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[O:8][CH:7]([CH3:15])[CH2:6][CH2:5][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O[C@H]2CCCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CCSc1ccccc1)O[C@H]1CCCCO1
Temperature: 25 °C

Procedure:
A solution of (2) (27.5 g) in EtOH (46 ml) was added dropwise during 10 min to a solution of PhSNa prepared from PhSH (11.2 ml) and Na (3.01 g) in EtOH (130 ml) with stirring at room temperature. The mixture was stirred and heated under reflux for 2.5 hr. The mixture was poured into iced 2N aqueous NaOH and extracted with ether. The ether solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give 22.3 g of (3).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:69])[NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:52]=[C:53]3[C:57](=[CH:58][CH:59]=2)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[CH2:54]3)=[CH:47][CH:46]=1>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:69])[NH:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[CH:52]=[C:53]3[C:57](=[CH:58][CH:59]=2)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[CH2:54]3)=[CH:49][CH:50]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccccc4F)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccccc4F)cc3)ccc2C1=O
Yield: 84 %

Procedure:
The compound of example 227 was prepared analogous to compound of example 225 by hydrolysis of compound of example 226.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)(O)[O-].[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=3)[CH2:28][C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])[N:21]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 25 %

Procedure:
To a mixture of 3-chloro-4-methyl-N-(4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (2.35 g, 7.3 mmol) and sodium bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating to reflux the reaction mixture for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.3 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.79 g, 25%) as a white solid: mp 201° C. Anal. Calc'd. for C18H16N2SO3F3Cl.0.5 PhCH3: C, 53.92, H, 4.21, N, 5.81. Found: C, 54.20, H, 4.19, N, 5.67.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CCCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCC(C)Oc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (92 mg) in dry MeOH (9.9 mL) was added 4N HCl in 1,4-dioxane (1.7 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralised to pH7 with 2M sodium hydroxide solution and concentrated in vacuo to give an off-white solid. The solid was triturated with water (30 mL) and filtered under reduced pressure to give the title compound as an off-white solid (55 mg).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8]>C(Cl)Cl>[CH3:6][S:7]([O:5][CH2:1][CH2:2][C:3]#[CH:4])(=[O:9])=[O:8]
Reactant: C#CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C#CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of but-3-yn-1-ol (45.0 g, 0.64 mol) and methanesulfonyl chloride (81.0 g, 0.71 mol) in 600 mL of DCM was added TEA (78.0 g, 0.77 mol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours then concentrated to dryness. The residue was dissolved in 1 L of EtOAc then washed with 1N HCl (2×200 mL), brine (200 mL), dried over anhydrous Na2SO4 and concentrated to afford but-3-yn-1-yl methanesulfonate.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.C1(C)C=CC=CC=1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 23 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.901 g; 4.00 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then toluene (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0564 g; 10 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in toluene (2 ml). The reaction mixture was then heated to 65° C. and stirred for 5 days; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.46 mmol (23% yield) of diphenylacetylene and 0.43 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: COc1ccc2c(c1C1=CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.9 %

Procedure:
A solution of tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.203 g, 0.587 mmol) synthesized in the same manner as that of Example B52, Step 1 in ethanol (10 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.100 g), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (0.0263 g, 13%).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:17](=[O:18])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1N
Agent: Cl
Product: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1

Procedure:
Following the procedure described for Example 330A Step 2, reaction of 3-tert-butyl-1-isobutyl-1H-pyrazol-5-amine hydrochloride with phenyl chloroformate, afforded phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate which was used in the subsequent step.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:18])[N:5]([C:9]1[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][N:13]=1)[N:6]=CC>O>[CH3:2][NH:3][C:4](=[O:18])[N:5]([C:9]1[S:10][C:11]([C:14]([F:15])([F:16])[F:17])=[N:12][N:13]=1)[NH2:6]
Reactant: CC=NN(C(=O)NC)c1nnc(C(F)(F)F)s1
Agent: Cl
Solvent: O
Product: CNC(=O)N(N)c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Concentrated hydrochloric acid (1.0 ml) was added to a stirred suspension of acetaldehyde 4-methyl-2-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)semicarbazone in water (200 ml). The mixture was stirred at room temperature for 3 days, and was filtered. The solid was dried and crystallised from ethyl acetate to give 4-methyl-2-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)semicarbazide (10.0 g) as a white solid, mp 181°-182° C.
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C2OC=C(CCO)N=2)[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])(C)(C)C.C(NCC[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)(=O)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:31]1([O:11][C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(=O)NCCc1ccc(O)cc1
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 109.7 %

Procedure:
To a stirred solution of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (5.51 g, 17.38 mmole) in tetrahydrofuran (47 ml) was added N-ethyl, N-propionyl tyramine (3.5 g, 15.8 mmole) and triphenylphosphine (4.55 g, 17.38 mmole). After cooling to 0° C., a solution of diethylazodicarboxylate (2.73 ml, 17.38 mmole) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stir for 22 hours, evaporated, and triturated with methylene chloride (50 ml) and filtered. The filtrate was chromatographed on silica gel twice using methylene chloride-ethyl acetate and hexane-acetone gradients to give the intermediate phenyl ether (2.95 g, 36%):
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=Cc1cccc(O)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1cccc(O)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 3 g of ethyl 2-hydroxy-6-vinylbenzoate (see Example 1a), 150 ml of methanol and 45 ml of 10% by weight sodium hydroxide solution was boiled for 8 h. It was then poured into ice-water at pH 1 (hydrochloric acid) and extracted with ethyl acetate, and the solution was dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.Br[CH2:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH:1]1([C:7]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[CH3:25])=[CH:15][N:9]3[C:8]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(F)cccc1CC(=O)CBr
Reactant: C1=CC(Cc2ccccn2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(F)cccc1Cc1cn2ccccc2c1C1CCCCC1
Yield: 64.2 %

Procedure:
The compound of step 1 (0.415 g, 2.37 mmol) and the compound of step 2 of example 1 (0.58 g, 2.37 mmol) were dissolved in 15 ml of acetone and the solution was stirred under reflux for 36 h. The solution was evaporated to dryness and the solid (0.92 g) dissolved in 10 ml of isopropanol. Sodium carbonate (0.70 g, 6.57 mmol) was added, the mixture was stirred under reflux for 2 h and then evaporated to dryness under reduced pressure. The residue was taken up in DCM and water, and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (HEP/EA, 100:0, then 70:30) to give 0.489 g of the title compound as a thick yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](O)=[CH:4][C:3]=1[NH:10][C:11]([CH3:13])=[O:12].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>[OH-].[K+].C(O)C>[C:11]([NH:10][C:3]1[CH:4]=[C:5]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:12])[CH3:13]
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCc1cc(NC(C)=O)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 74.8 %

Procedure:
In a solution of 5.6 g of potassium hydroxide in 200 ml of ethanol was dissolved 22 g of 4,6-dichloro-3-acetaminophenol (which was synthesized using the method described in Beilstein, 13, I, 135). To the solution was added 30.5 g of hexadecyl bromide. After the mixture was stirred for an hour at room temperature (about 20-30° C.), the mixture was heated at reflux for 8 hours. The reaction mixture was poured into water. The resulting precipitate was recovered by filtration and washed with methanol to obtain 32 g of the desired product. The melting point thereof was 92 to 93.5° C.