Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:36][CH2:37][CH2:38][CH2:39]Cl)=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:36][CH2:37][CH2:38][CH2:39][N:52]2[CH2:51][CH2:50][N:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][CH3:41])[CH2:54][CH2:53]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccc(COc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc2OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCOc2cc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)ccc2OCc2ccc(C)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
3-[4-(4-Methylphenylmethoxy)-3-(3-chloropropoxy) benzoyl]-1-(phenylsulfonyl)indole (0.44 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (5 ml). 1-(2-Methoxyphenyl)piperazine (0.20 g), potassium carbonate (0.14 g), and potassium iodide (0.38 g) were added to the resultant solution and the mixture was stirred overnight at 60° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:3), obtaining 0.29 g of 3-{4-(4-methylphenylmethoxy)-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}-1-(phenylsulfonyl)indole (0.29 g) as a light yellow oily substance.
Reaction SMILES: [CH2:1]1[O:25][C:4]([O:23]C)([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:6]=2)[O:3][CH2:2]1.[OH-].[Na+]>O>[CH2:2]1[O:3][C:4]([OH:23])([C:5]2[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:9][CH:10]=2)[O:25][CH2:1]1
Reactant: COC1(c2ccc(OCCCC(=O)c3ccccc3)cc2)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCOc1ccc(C2(O)OCCO2)cc1)c1ccccc1
Temperature: 20 °C
Yield: 81.5 %

Procedure:
Methyl 4-(4-oxo-4-phenylbutoxy)benzoate ethylene acetal (27.0 g), denatured alcohol (90 mls), water (90 ml) and sodium hydroxide (9.0 g, 0.225 moles) were heated at reflux for 3 hours. The mixture was cooled to 20° C., diluted with water (250 ml) and extracted with toluene (2×250 ml). The aqueous phase was acidified with concentrated hydrochloric acid (35 ml) and the precipitate filtered, washed with water and dried to give 4-(4-oxo-4-phenylbutoxy)benzoic acid ethylene acetal (21.1 g, 70% from 4-chlorobutyrophenone).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](OB(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[S:17][CH:18]=1)=[O:30]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COC(=O)c1cc(I)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Yield: 57.2 %

Procedure:
Under nitrogen atmosphere, 2-(2-{2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)-5-iodobenzoic acid methyl ester (5.0 g) synthesized in Example 92-1 and 4-fluorophenylboric acid (1.5 g) were dissolved in dioxane (40 mL) and aqueous sodium carbonate solution (2 mol/L, 20 mL), tetrakis(triphenylphosphine)palladium (0.51 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.7 g) as a colorless oil.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5]([CH2:19][OH:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1.[H][H]>CCOC(C)=O.O=[Pt]=O>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5]([CH2:19][OH:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 98.2 %

Procedure:
A solution of 1 g (2.49 mmol) of alcohol 4 in 13 mL of EtOAc and Adam's catalyst (22 mg) was stirred under 30 psi of hydrogen gas in a Parr apparatus over 21 h. The mixture was then filtered to remove the catalyst through a plug of silica gel with EtOAc as solvent. The filtrate was then concentrated in vacuo yield the propyl ester 11 (990 mg) as an oil; 1H NMR (CDCl3); 0.94 (t, J=7.3 Hz, 3H), 1.20-1.94 (m, 31H), 2.17 (m, 2H), 2.32 (m, 4H), 3.46-4.12 (m, 8H), 4.03 (t, J=6.6 Hz, 2H), 4.13-4.38 (m, 2H), 4.59 (m, 1H), 4.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][C:16]=1[O:29][CH3:30].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:13][C:11]3[N:10]([N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:12]=3)[C:23](=[O:24])[CH:22]=2)=[CH:17][C:16]=1[O:29][CH3:30]
Reactant: Nc1nc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: COc1cc(-c2cc(=O)n3nc(-c4ccc(Cl)cc4)nc3[nH]2)ccc1Cl
Temperature: 130 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.51 mmol) in n-BuOH (1 ml) was added ethyl 3-(4-chloro-3-methoxyphenyl)-3-oxopropanoate (200 mg, 0.78 mmol) and TsOH (5 mg, 0.02 mmol), and the resulting mixture was stirred overnight at 130° C. The solids were collected by filtration and washed with methanol (2×5 ml) to afford 5-(4-chloro-3-methoxyphenyl)-2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (56.6 mg, 28%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.[C:11]([OH:17])(=O)[CH2:12][C:13]([OH:15])=O.[OH-].[Na+]>>[OH:15][C:13]1[C:10]2[C:3](=[CH:4][CH:5]=[C:6]([O:7][CH3:8])[CH:9]=2)[N:2]([CH3:1])[C:11](=[O:17])[CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: CNc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)c(O)cc(=O)n2C
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To a mixture of N-methyl-p-anisidine (2.8 g, 20 mmol) and malonic acid (4.3 g, 40 mmol) was added POC13 (17 mL). After heating at 90° C. for 1.5 hr, the reaction mixture was poured over ice and basified with 6N NaOH to a pH of 14. The solution was then filtered and the filtrate was acidified with 6N HCl to pH 3. The precipitate was filtered and dried to afford a brown solid (1.8 g, 50%). 1H NMR (300 MHz, MeODd4) 8 3.65 (3H, s), 3.86 (3H, s), 5.97 (1H, s), 7.28 (1H, dd, J=2.8, 9.3 Hz), 7.49 (2H, d, J=9.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH:19]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(C=Cc2ccccc2)csc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
2-t-Butoxycarbonylamino-4-styryl-thiophene-3-carboxylic acid ethyl ester (0.335 g, 0.848 mmol) was dissolved in anhydrous CH2Cl2 (8 mL). This was treated with trifluoroacetic acid (0.346 mL, 4.49 mmol) and stirred at room temperature for 6 hr. More trifluoroacetic acid (0.346 mL, 4.49 mmol) was added and stirring at room temperature was continued for 30 min. The reaction was neutralized with sat. NaHCO3 (25 mL) and then extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with H2O (1×25 mL) and brine (1×25 mL). The organic layer was then dried (Na2SO4), filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (SiO2, 15 EtOAc/85 hexanes) to afford the title compound (0.1298 g, 56%) as an inseparable mixture. MS m/e (CI) 274.0 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 0.85 (d, 1H), 1.32 (m, 4H), 4.26 (m, 1H), 6.75 (s, 1H), 7.18 (m, 4H), 7.35 (d, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 7.78 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([S:20]([C:18]3[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=3[O:24][CH3:25])(=[O:21])=[O:22])[C:6]=2[CH:12]=1
Reactant: Brc1ccc2c(c1)NCCCC2
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCCc2ccc(Br)cc21

Procedure:
8-Bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine was reacted with 5-chloro-2-methoxybenzenesulfonyl chloride in analogy to example 34, step 2, yielding 8-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine. Off-white solid, MS (ISP): m/e 430.2 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:15]#[CH:16]>C(NCC)C.[Cu]I>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][CH2:14][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Ic1ccc(N2CCCCC2)cc1
Reactant: C#CCOCCCCCCO
Agent: [Cu]I
Solvent: CCNCC
Product: OCCCCCCOCC#Cc1ccc(N2CCCCC2)cc1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 1-(4-iodophenyl)piperidine (1.5 g), 6-[(2-propynyl)oxy]-1-hexanol (820 mg), BTPC (35 mg) and copper (I) iodide (20 mg) in diethylamine (30 ml) under nitrogen, was stired at room temperature overnight. The solvent was evaporated and the residue was partitioned between EA (50 ml) and 8% aqueous sodium bicarbonate (50 ml). The organic layer was washed with water and brine, dried and concentrated to a dark oil which was purified by FCC eluting with ER to give the title compound as an orange oil (1.2 g), t.l.c. (ER) Rf 0.70.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15](=[O:31])[CH2:16][C@@H:17]([CH2:29]I)[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[C:10]([O:14][C:15](=[O:31])[CH2:16][C@@H:17]([CH2:29][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])([CH3:13])([CH3:11])[CH3:12]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiophenol (0.15 ml) in N,N-dimethylformamide (6 ml) was added NaH (58 mg) under ice cooling. After stirring at room temperature for 30 minutes, N-(benzyloxycarbonyl)-3(S)-iodomethy-β-alanine tert-butyl ester (0.6 g) was added and stirred for additional 1 hour. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% (EtOAc/n-hexane) to give N-(benzyloxycarbonyl)-3(S)-phenylthiomethy-β-alanine tert-butyl ester (0.64 g) as an pale yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[CH2:12]([S:14][C:15]1[N:20]=[C:19](Cl)[C:18]([C:22]#[N:23])=[CH:17][N:16]=1)[CH3:13]>CN(C=O)C.O>[CH2:12]([S:14][C:15]1[N:16]=[C:17]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[C:18]([C:22]#[N:23])=[CH:19][N:20]=1)[CH3:13]
Reactant: CCSc1ncc(C#N)c(Cl)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ncc(C#N)c(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.9 %

Procedure:
To a suspension of sodium hydride (31 mg, 0.78 mmol) in DMF (2.5 mL) at 0° C. was added benzimidazole (86 mg, 0.72 mmol). After stirring for 5 min, the reaction mixture was warmed to room temperature. To this was added 2-ethylthio-4-chloro-5-cyanopyrimidine (130 mg, 0.65 mmol) dissolved in DMF (1.0 mL), then the mixture was heated at 100° C. for 1 h. The reaction mixture was cooled and carefully diluted with H2O. The aqueous layer was extracted with EtOAc several times, and the combined extracts were washed with brine. After drying over Na2SO4, the crude material was purified by flash chromatography using 1:7 acetone:hexane system to give 126 mg of the title compound. Mass spectrum 282.2 (ESI, M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:15](Cl)(Cl)=[O:16]>O>[CH3:12][O:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15](=[O:16])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2[nH]c(=O)oc(=O)c12

Procedure:
A solution of 2-amino-6-methoxybenzoic acid (10 g, 60 mmol), water (330 mL), and sodium hydroxide (7.2 g, 176 mmol) was treated with phosgene (20% solution in toluene, 82 mL, 164 mmol) over 1 hour and filtered. The filter cake was dried to provide the desired product. MS (ESI(+)) m/e 194 (M+H)+, 211 (M+NH4)+, 216 (M+Na)+; (ESI(−)) m/e 192 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.64 (t, 1H), 6.84 (d, 1H), 6.68 (d, 1H), 3.88 (s, 3H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[N:20][N:19]=1>C(Cl)Cl.CO>[N:23]1([C:21]2[S:22][C:18]([C:8]3[CH:9]=[CH:10][C:11]([N:13]4[CH:17]=[CH:16][CH:15]=[N:14]4)=[CH:12][C:7]=3[OH:6])=[N:19][N:20]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: COc1cc(-n2cccn2)ccc1-c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1cc(-n2cccn2)ccc1-c1nnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
BBr3 (1M solution in heptane, 1.56 mL, 1.56 mmol) was added to a stirred, nitrogen flushed solution of tert-butyl 4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (138 mg, 0.312 mmol) in DCM (6 mL) and the resulting bright yellow suspension was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of MeOH (10 mL) to give a suspension. The solid was collected by vacuum filtration, rinsed with MeOH, and re-dissolved in a mixture of DMSO and water. The solution was loaded onto a 5 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with DMSO/water (5 mL), MeOH (20 mL), then flushed with 7M NH3 in MeOH (30 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as an off-white solid. The crude material was sonicated in MeOH (5 mL) and the resulting suspension filtered under vacuum to afford the title compound as an off-white solid (69 mg, 68% yield). LC-MS: Rt 0.76 min; MS m/z 329.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J=2.53 Hz, 1H), 8.03 (d, J=8.59 Hz, 1H), 7.77 (d, J=1.52 Hz, 1H), 7.52 (d, J=2.02 Hz, 1H), 7.42 (dd, J=8.59, 2.02 Hz, 1H), 6.55-6.61 (m, 1H), 3.42-3.48 (m, 4H), 2.80-2.91 (m, 4H).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[I:16][CH2:17][CH2:18][CH2:19][CH2:20]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[I:16][CH2:17][CH2:18][CH2:19][CH2:20][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:15])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=S1(=O)CCN(c2ccc(OCCCCI)cc2)CC1
Reaction time: 4 h

Procedure:
A mixture of 4-(1',1'-dioxothiomorpholino)phenol (10 g, 44 mmol), 1,4-diiodobutane (40.9 g, 132 mmol) and cesium carbonate (42.9 g, 132 mmol) was heated at 50° C. in acetonitrile (400 ml). After 4 hours, the reaction mixture was cooled, filtered and the solid salts washed with acetonitrile. The filtrate was poured into dilute HCl/ice water (1.2 l) and the resultant cream colored solid was isolated by filtration and washed with water. Chromatography on silica gel, with 97:3; dichloromethane:ether, afforded 1-iodo-4-[4'-(1,1-dioxothiomorpholino)phenoxy] butane, II (13.4 g, 74%). Mp. 119-121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(F)c2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenyl}-2-propenoate (140) (0.235 g, 0.54 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, compound 141 was obtained as pale yellow solid (0.182 g, 83%). mp 193-195° C. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.88 (s, 2H), 1.91 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.76 (dd, J1=8.2 Hz, J2=1.6 Hz, 1H), 6.80-6.92 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 9.72 (s, 1H), 12.32 (s, 1H). LCMS (ES): m/z 407 (M−H)−. Anal. Calcd for C26H29FO3.⅙H2O: C, 75.89; H, 7.19; Found: C, 75.91; H, 7.17.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][SH:13])=[CH:10][CH:9]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].[I-].[K+]>CC(C)=O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:13][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCc1ccc(Cl)cc1
Yield: 100 %

Procedure:
Anhydrous acetone (100 ml), potassium carbonate (21 g), p-chlorobenzylmercaptan (19.5 ml), methyl chloroacetate (13.2 ml) and potassium iodide (0.1 g) are mixed in the cold. The mixture thus obtained is stirred and heated under reflux for 7 hours. It is cooled, the precipitate (K2CO3) is filtered off, the acetone is evaporated from the filtrate and the residue is taken up with ether. The ether solution is washed with 4 N NaOH and then with water until the wash waters have a neutral pH. The ether solution is then dried over MgSO4, the ether is evaporated and 34.5 g (100% yield) of methyl p-chlorobenzylmercapto-acetate are collected in the form of a chromatographically pure oil.
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=[C:5]([Cl:19])[C:4]=1[CH3:20].[CH2:21]([O:23][CH:24]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[CH3:25])[CH3:22]>O.C1(C)C=CC=CC=1.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>[Cl:19][C:5]1[C:4]([CH3:20])=[C:3]([C:29]2[CH:28]=[N:27][N:26]([CH:24]([O:23][CH2:21][CH3:22])[CH3:25])[CH:30]=2)[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cccc(F)c2)cn1
Temperature: 80 °C
Yield: 31.8 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.049 g, 0.58 mmol) in water (1 mL) was added a solution of 1-(6-bromo-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.29 mmol) in toluene (1 mL) followed by 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.093 g, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol). The resulting mixture was bubbled with N2 for 5 min and then heated at 80° C. over a weekend. The organic layer was concentrated and purified on silica gel (eluting with 0-30% of ethyl acetate in hexanes) to give the desired product (37 mg, 32%). LCMS calculated for C22H23ClFN2O2 (M+H)+: m/z=401.1. found: 401.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OC)=[O:19].[CH:22]([C:25]1[N:30]=[C:29]([OH:31])[CH:28]=[C:27]([CH3:32])[N:26]=1)([CH3:24])[CH3:23]>>[CH:22]([C:25]1[N:30]=[C:29]([O:31][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)[S:5][C:4]=2[CH2:18][OH:19])[CH:28]=[C:27]([CH3:32])[N:26]=1)([CH3:24])[CH3:23]
Reactant: Cc1cc(O)nc(C(C)C)n1
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Product: Cc1cc(OCc2cc(-c3ccc(C(F)(F)F)cc3)sc2CO)nc(C(C)C)n1

Procedure:
The title compound was prepared using methyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 132) and 2-isopropyl-6-methyl-4-pyrimidinol.