Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([OH:20])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C([O-])(O)=O.[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O.O1CCOCC1>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([OH:20])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][N:15]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7]
Reactant: N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
3 g (10 mmols) of Glu-His-OH and 2.3 g of NaHCO3 are dissolved in 20 ml of water and, while stirring at room temperature, a solution of 2.1 g (10% excess) of p-toluene sulfochloride in about 10 ml of dioxane is slowly added drop by drop. When the addition is terminated, stirring of the mixture is continued for a further hour, whereupon it is extracted twice with ether. The aqueous phase is acidified to pH 2 with 2 N HCl and the precipitate is filtered off with suction. It is washed with water and the filer residue is dried over P2O5 under reduced pressure. Yield 2.2 g.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[CH:10]=1.[CH3:17][S:18]SC>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([S:18][CH3:17])=[C:11]([CH3:16])[CH:10]=1
Reactant: CSSC
Reactant: Cc1cc(Cl)ccc1N
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1ccc(Cl)cc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 908.2 %

Procedure:
t-Butyl nitrite (1.52 g) was added to a mixture of 4-chloro-2-methylaniline (2.0 g) and dimethyl disulphide (14.49 g) in chloroform. The mixture was heated to 70° C. to initiate the reaction. A solution of 4-chloro-2-methylaniline (9.0 g) in chloroform and t-butyl nitrite (7.25 g) were added simultaneously while maintaining the temperature in the range 60°-70° C. Further dimethyl disulphide (11.83 g) was added followed by the simultaneous addition of a solution of 4-chloro-2-methylaniline (9.0 g) in chloroform and t-butyl nitrite (7.25 g) while maintaining the temperature in the range 50°-55° C. The mixture was stirred at room temperature for 2 hours. It was washed thoroughly with water, 2M hydrochloric acid, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 5-chloro-2-(methylsulphenyl)toluene (22.15 g) as a red oil which was not further characterized.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[O:21])=[C:15]([Cl:30])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:29][C:26]1[N:25]=[CH:24][C:23]([NH:22][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][C:15]=2[Cl:30])=[O:21])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)Nc3ccc(Cl)nc3)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)nc1)Nc1ccc(C2CCNC2)cc1Cl
Temperature: 25 °C
Reaction time: 34 h
Yield: 17 %

Procedure:
To a stirred suspension of (RS)-3-{3-chloro-4-[3-(6-chloro-pyridin-3-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (68 mg) in dichloromethane (6 ml) was added trifluoroacetic acid (92 μl) and the reaction mixture was then stirred at room temperature for 34 h. The reaction mixture was then poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: heptane/EtOAc/MeOH) to afford (RS)-1-(6-chloro-pyridin-3-yl)-3-(2-chloro-4-pyrrolidin-3-yl-phenyl)-urea (9 mg, 17%) as an off-white solid. MS (ISP): 355.1 ([{37Cl}M+H]+), 353.1 ([{37Cl35Cl}M+H]+), 351.2 ([{35Cl}M+H]+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH2:3]1.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>C(OCC)(=O)C.O>[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([S:55]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:8]=3)[CH2:3]2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (-)-(2-aminoindan-5-yl)acetate.(-)-dibenzoyl-L-tartaric acid salt (3.94 g) is added to a mixture of potassium carbonate (4.83 g), water (50 ml) and ethyl acetate (70 ml), and 4-chlorophenylsulfonyl chloride (1.49 g) is added thereto. The mixture is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with an aqueous sodium hydrogen carbonate solution, dried, and distilled under reduced pressure to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and hexane to give methyl (-)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (2.43 g) as colorless crystals.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Zn](CC)CC.[C:14]1(C)[CH:19]=CC=C[CH:15]=1>>[CH3:19][C:14]([C@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[OH:8])=[CH2:15]
Reactant: O=CC1CCCCC1
Reactant: Cc1ccccc1
Agent: CC[Zn]CC
Product: C=C(C)[C@@H](O)C1CCCCC1
Temperature: 0 °C
Yield: 90 %

Procedure:
Into a 20-mL scintal vial 46.5 mg (0.41 mmol) cyclohexanecarboxaldehyde was added dropwise (neat) and diluted with 1.5 mL toluene in a nitrogen atmosphere glovebox. A dry and thoroughly purged (N2) 10 mL Schlenk flask capped with a rubber septum was charged with 4.0 mg (0.017 mmol) (−)-MIB and a stir bar. In the glovebox, 65.5 mg (0.44 mmol) 3 was weighed into the Schlenk flask and the solids diluted with toluene (2 mL). 3.1 eq. (125 μL, 1.23 mmol) Et2Zn was then added neat. The flask was cooled to 0° C. and the aldehyde was added dropwise under an N2 purge. The reaction was stirred until judged complete by TLC and then quenched with saturated NH4Cl (6 mL). The clear biphasic layers were partitioned and the aqueous layer was repeatedly extracted with diethyl ether (3×25 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica (70:20:10, hexanes:CH2Cl2:EtOAc) to afford the title compound as a colorless oil in 90% yield (58 mg, 0.37 mmol). [α]D20=−16.7 (c=0.104, CHCl3, 92% ee). 1H NMR (C6D6, 500 MHz): δ.0.88-0.98 (m, 2H; methylene), 1.09-1.17 (m, 3H; methylene), 1.18 (br, 1H; OH), 1.35 (m, 1H; methylene), 1.46 (m, 1H; methylene), 1.58 (m, 1H; methylene), 1.59 (s, 3H; CH3), 1.64 (m, 1H; methylene), 1.71 (m, 1H; methylene), 2.01 (m, 1H; methylene), 3.54 (d, 4 Hz, 1H; RCHOH), 4.78 (s, 1H; alkene), 4.84 (s, 1H; alkene) ppm. 13C{1H} NMR (C6D6, 125 MHz): δ.17.88, 26.81, 26.98, 27.25, 29.02, 30.39, 41.25, 81.16, 112.26, 147.48 ppm. IR (neat): 3383 (OH), 2919, 2848, 1648, 1446, 1372, 1260, 1080, 1019 cm−1. LRMS-CI m/z 136.13 [(M−□□□)+; calcd for; C10H17: 136.13].
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:39])[C:7]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)([CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)C.C(OC(=O)C(C)(OC1C=CC=CC=1)CC1C=CC(OCCC2N=C(C3CCCCC3)OC=2C)=CC=1)C>C(O)C>[Br:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[O:31][C:7]([CH3:30])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[C:6]([OH:39])=[O:5]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1cccc(Br)c1
Agent: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(Br)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
5N NaOH (0.5 mL) was added to a solution of 2-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid ethyl ester and 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester in ethanol (4 mL). The resultant mixture was refluxed under an atmosphere of nitrogen for 2 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo, diluted with 1N HCl, and extracted with CH2Cl2. The organic layer was dried through a Varian ChemElut cartridge, concentrated in vacuo, and purified by LCMS. 1H NMR (400 MHz, CDCl3): δ 7.17 (m, 5H), 6.90-6.76 (m, 3H), 4.12 (t, 2H, J=6.26 Hz), 3.22 (d, 1H, J=13.69 Hz), 3.10 (d, 1H, J=13.69 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.90-2.68 (m, 1H), 2.30 (s, 3H), 2.01 (d, 2H, J=13.30 Hz), 1.79 (d, 2H, J=12.90 Hz), 1.69 (d, 1H, J=13.30 Hz), 1.40 (s, 3H), 1.58-1.21 (m, 4H). MS [EI+] 543 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].C(N(CC)CC)C.O>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:7]
Reactant: O=C(Cl)c1ccsc1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of this crude thiophene-3-carbonyl chloride (97.7 g, 666 mmol) and N,O-dimethylhydroxylamine hydrochloride (71.5 g, 733 mmol) in dichloromethane (600 mL) at 0° C. was added dropwise triethylamine (186 mL, 1.33 mol). After stirring at room temperature for 3 h, the reaction mixture was poured into water (2 L), the layers were separated and the aqueous layer extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (200 mL), then dried over MgSO4 and concentrated in vacuo to afford N-methoxy-N-methylthiophene-3-carboxamide [102.2 g, yield 90%; HPLC/MS: m/z=172 (M+H); log P(HCOOH)=1.30].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[O:1]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2)[Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC1Cc2cccc(O)c2C1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cccc(O[Si](C)(C)C(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-hydroxy-2-methyl-1-indanone (6) (10.2 g, 37 mmol) and imidazole (3.02 g, 44 mmol) dissolved in DMF (200 ml) was added tert-butyldimethylchlorosilane (6.11 g, 41 mmol) in DMF (50 ml). The reaction mixture was stirred overnight at room temperature and treated with water (200 ml) and extracted with diethylether (2×200 ml). The combined organic phases were washed with aqueos NH4Cl (300 ml), brine (100 ml) and dried over sodium sulfate. Evaporation gave (7) as a yellow oil which was used without further purification.
Reaction SMILES: CN(C)C1C=CC([N+]([O-])=[CH:10][C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[N:14]=[CH:13][C:12]=2[C:27]#[N:28])=CC=1.Cl.C(OCC)(=[O:34])C>>[C:27]([C:12]1[CH:13]=[N:14][N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:11]=1[CH:10]=[O:34])#[N:28]
Reactant: CCOC(C)=O
Reactant: CN(C)c1ccc([N+]([O-])=Cc2c(C#N)cnn2-c2ncc(C(F)(F)F)cc2Cl)cc1
Agent: Cl
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=O

Procedure:
To a stirred suspension of 7.6 grams (0.02 mole) of N-[4-(dimethylamino)phenyl]-a-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]nitrone in 300 mL of ethyl acetate was added 400 mL of aqueous 6N hydrochloric acid, at which time all of the solid material dissolved. The aqueous layer was separated and extracted with one portion of ethyl acetate. An aqueous solution saturated with sodium chloride was added to the aqueous layer, and the mixture was extracted several more times with ethyl acetate. The ethyl acetate extracts were combined with the organic layer, and the combination was washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was cooled and triturated with heptane, yielding 2.5 grams of 4-cyano-5-formyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure. (The compounds of Steps E, F, and G were prepared by the method of E. C. Taylor et al., J. Org. Chem., 43, 4, 736 (1978).)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]([CH2:24][C:25]([NH:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[O:26])[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cccc(Cl)c2C)cc1
Reactant: COc1ccc(CNC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(OC)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.7 %

Procedure:
220 mg of methyl 4-{[(3-chloro-2-methylphenyl)amino]sulfonyl}benzoate was dissolved in 1.10 mL of DMF, and 168 mg of 2-bromo-N-(4-methoxybenzyl)acetamide and 100 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 7 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 4:6) to obtain 270 mg of methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate. The obtained methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate was dissolved in 2.00 mL of methanol and 1.50 mL of THF, and 1.05 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 days. The reaction liquid was acidified by addition of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 90:10) to obtain 204 mg of 4-[((3-chloro-2-methylphenyl) {2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32](O)[C:33]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][O:36][C:35]=2[CH:34]=1>>[O:38]1[C:39]2[CH:40]=[CH:41][C:33]([CH2:32][O:20][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([NH:22][C:23](=[O:31])[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=3)=[O:21])=[CH:34][C:35]=2[O:36][CH2:37]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1NC(=O)Cc1ccccc1
Yield: 73.3 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.26 g, 1.7 mmol), 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid from Example 10, Step 1 (0.3 g, 1.1 mmol), and piperonyl alcohol (0.17 g, 1.1 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 0.33 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester. A sample of the product was stirred in 2 M aqueous KHCO3 for several hours, filtered off, rinsed with water, and dried to give product with a mp 191-195° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.O>CS(C)=O.C(OCC)(=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1cccc(Oc2nnc(Cc3ccncc3)c3ccccc23)c1

Procedure:
Under exclusion of air, 200 mg (0.78 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67A.1), 173 mg (1.25 mmol) K2CO3, and 120 mg (0.94 mmol) 3-chlorophenol (Fluka) are heated in 2 ml DMSO for 3 h to 90° C. The reaction mixture is distributed between 20 ml water and 20 ml ethyl acetate, and the aqueous phase separated and extracted with 2 portions of ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4), and concentrated by evaporation. The residue is dissolved in ≦15 ml THF, precipitated with hexane, and filtered. Title compound is obtained from the evaporated filtrate after chromatography (SiO2; ethyl acetate/CH3OH, 4:1): m.p.: 143-145° C.; HPLC: tRet(Grad20-100)=8.9; FAB MS (M+H)+=348.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.7 %

Procedure:
In DMF (150 ml) was dissolved 4-bromophenol (25 g). To the mixture was added potassium carbonate (30 g) and then was added dropwise 3-bromopropanol (26.1 g), and the mixture was stirred at 100° C. for 20 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 3-(4-bromophenoxy)-1-propanol (20.6 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[F:10][C:11]1[CH:12]=[C:13]([SH:19])[CH:14]=[CH:15][C:16]=1OC.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([S:19][CH2:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[CH3:9])[CH:14]=[CH:15][C:16]=1[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S)cc1F
Reactant: CN1CCCC1CCCl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(SCCC2CCCN2C)cc1F
Yield: 74.2 %

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (1.4 g, 9.48 mmole), 3-fluoro-4-methyoxythiophenol (1.5 g, 9.48 mmole), potassium carbonate (13.1 g, 94.8 mmole) and DMF (20 mL) were combined, yielding 1.90 g (7.03 mmole, 74%) of the desired compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](=O)[NH:5][C:6](=O)[NH:7][CH:8]=1.P(Cl)(Cl)([Cl:15])=O.P(=O)(O)(O)O.C(N(C(C)C)CC)(C)C.[ClH:32]>C(OCC)C>[Cl:32][C:6]1[N:5]=[C:4]([Cl:15])[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: Cl
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P(O)(O)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cnc(Cl)nc1Cl
Temperature: 100 °C
Yield: 95 %

Procedure:
5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 min at such a rate that the internal temperature of the reaction reached 85–90° C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100° C. for 20 h, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40° C. and then added dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15° C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5×1.5 L washes), dried with MgSO4 and concentrated to provide 288 g (95% yield) of a light yellow-orange oil of 96% purity (HPLC). This material can be further purified by distillation (bp 109° C. at 79 mmHg).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].N#N.[OH-].[Na+].[CH2:17](Cl)[CH:18]=[CH2:19]>O.CC(O)C>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH:8]=[CH2:9])[CH:5]=[CH:4][C:2]=1[O:3][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCl
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=CCOc1ccc(CC=C)cc1OC
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A multi-necked round bottom flask equipped with mechanical stirrer, thermometer, reflux condenser and dropping funnel was charged with 150 g of eugenol, 400 ml of 2-propanol and a gentle flow of N2 was introduced. A 40% NaOH solution (43.9 g NaOH, 1.1 mole in 66 g H2O) was added slowly to the externally cooled reaction vessel at a rate to maintain the internal temperature below 35° C. The mixture was stirred for 10 minutes and 113 ml (1.38 mole) of allyl chloride was added to the flask and heated to maintain a gentle reflux for 1 hour, at which time the reaction was complete (GC analysis). The flask was charged with 300 ml water. A Dean-Stark Trap and steam bath were used to azeotropically remove the 2-propanol. The distillation ceased when the temperature reached 94° C. and after cooling, 300 ml of hexane was added and the water layer separated. The organic layer was washed with water until the pH of the water wash was neutral, the layer was then dried over MgSO4, filtered and the solvent removed under vacuum. The product was vacuum distilled to yield 155 g (84%) of a pale yellow 3-[2-methoxy-4-(2-propenyl)phenoxy]propene.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:8]([C:11]1[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C1C=C(Cl)CCC1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C=C(Oc2ccccc2)CCC1

Procedure:
To a stirred solution of 3-chloro-cyclohex-2-enone (3.00g, 23.0 mmol) and phenol (2.16 g, 23.0 mmol) in 25 mL of acetone was added powdered, anhydrous K2CO3 (3.81 g, 27.6 mmol). After refluxing for 18 h, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica gel eluting with hexanes/EtOAc (4:1) to give 3-phenoxy-cyclohex-2-enone as a white solid: 1H NMR (CDCl3) δ 2.10 (quint, 2H, J=6.3 Hz), 2.40 (t, 2H, J=6.2 Hz), 2.68 (t, 2H, J=6.3 Hz), 5.14 (s, 1H), 7.05 (d, 2H, J=7.5 Hz), 7.26 (t, 1H, J=7.3 Hz), 7.41 (t, 2H, J=7.6 Hz).