Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH2:23][CH2:24]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 5 was prepared according to procedures described in Example 3 substituting tert-butyl 4-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)piperidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.23 (d, J=7.70 Hz, 1 H), 6.09 (dd, J=7.70, 2.75 Hz, 1 H), 6.01 (d, J=2.75 Hz, 1 H), 4.87-4.98 (m, 1 H), 4.23 (app brs, 2 H), 3.85 (d, J=6.05 Hz, 2 H), 3.09 (s, 3 H), 2.79 (t, J=12.65 Hz, 2 H), 1.87-2.06 (m, 1 H), 1.76-1.87 (d, J=12.10 Hz, 2 H), 1.18-1.37 (m, 6 H), 1.25 (d, J=6.05 Hz, 6 H). MS (ESI) 449 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:13](I)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:15][CH:14]=[CH2:13])=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ccc(F)cc21
Reaction time: 3 h

Procedure:
A mixture of 7-fluoro-2(1H)-quinoxalinone (3.84 g, 23 mmol), allyl iodide (2.39 mL, 25.5 mmol) and potassium carbonate (9.56 g, 69.3 mmol) in dimethylformamide (60 mL) was stirred at room temp. for 3 h., then evaporated. The residue was dissolved in dichloromethane/water and the phases were separated. The aqueous phase was extracted (3×) with dichloromethane and the organic fractions were dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:12]=[CH:11][C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH3:26][O-:27].[Na+].CO>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[N:8][N:7]([C:9]3[C:10]([OH:23])=[C:11]([CH2:10][C:11]4[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([N:7]5[N:6]=[C:5]6[CH:24]=[CH:25][CH:2]=[CH:3][C:4]6=[N:8]5)[C:26]=4[OH:27])[CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=3)[N:6]=2)[CH:5]=[CH:24][CH:25]=1
Reactant: C[O-]
Reactant: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: C=C(C)C(=O)OCCc1cc(Cc2cc(C)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3cccc(Cl)c3n2)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Ten grams (30.9 mmols) of crude 2-(3'-N,N-diethylaminomethyl-2'-hydroxy-5'-methylphenyl)-2H-benzotriazole obtained following the procedures of Synthesis Example 1 and 11.1 g (31.0 mmols) of 5-chloro-2-(2'-hydroxy-5'-methacryloyloxyethylphenyl)-2H-benzotriazole were dissolved in 64 ml of xylene, and 1.5 ml of a 28% sodium methylate-methanol solution were added thereto. The mixture was then refluxed in a nitrogen stream for 10 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. Yellow crystals precipitated at this stage were separated through filtration, and recrystallized from chloroform to obtain 13.1 g of 6-(4-chloro-2H-benzotriazol-2-yl)-4-methacryloyloxyethyl-2-[3'-(2H-benzotriazol-2-yl)-2'-hydroxy-5'-methylphenyl]methylphenol (hereinafter abbreviated as "RUVA-2") as white crystals (yield 70.3%, purity 98.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]=[CH:6][C:5]1=2.C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[N:25]1([CH2:2][CH2:3][CH:4]2[CH2:12][CH2:11][CH2:10][C:9]3[N:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=[CH:6][C:5]2=3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: ClCCC1CCCc2c1cnn2-c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(-n2ncc3c2CCCC3CCN2CCOCC2)cc1
Yield: 75.9 %

Procedure:
A mixture of 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol), K2CO3 (336 mg, 2.43 mmol), morpholin (0.42 mL, 4.87 mmol) and a catalytic amount of KI in 20 mL of DMF is heated to reflux during 18 hours. The solvent is eliminated at reduced pressure, the crude is diluted with ethyl acetate, washed with water, and the organic phase is evaporated at reduced pressure. The resultant crude is purified by chromatography on silica-gel to obtain 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole (384 mg, 1.23 mmol, 76%, oil)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([F:19])[CH:12]=3)[N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[F:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl.CO>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:36][CH2:37][CH2:38]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:47]4[CH2:48][CH2:49][CH:44]([F:43])[CH2:45][CH2:46]4)=[C:13]([F:19])[CH:12]=3)[N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: FC1CCNCC1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(C=O)c(F)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(CN5CCC(F)CC5)c(F)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 4 mL reaction vial was added 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorobenzaldehyde (Example 30A) (53 mg, 0.085 mmol), 4-fluoropiperidine, hydrochloric acid (35.46 mg, 0.255 mmol), methanol (0.5 ml), dichloromethane (0.5 ml), and a few drops of acetic acid. The reaction mixture was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (53.82 mg, 0.255 mmol) was added. The reaction was stirred at room temperature overnight and then carefully quenched by addition of saturated sodium bicarbonate solution (about 400 μL) and dichloromethane (about 1 mL). The organic layer was collected, and the aqueous layer extracted with dichloromethane (2×1 mL). The combined organics were concentrated to give the title compound, which was used without further purification. MS APCI(+) m/z 713.42 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]2[C:4]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)([CH2:5]2)[C:3]1=[O:18]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]23[CH2:5][CH:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3]3=[O:18])=[CH:14][CH:13]=1
Reactant: CN1C(=O)C2CC2(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O

Procedure:
A solution of 1.5 g of 3-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 50 ml of ethanol is hydrogenated in the presence of 0.1 g of 5% palladium on carbon. When the hydrogenation is complete, the catalyst is removed and the filtrate is concentrated and the residue is recrystallised from ethyl acetate/petroleum ether. The title compound is obtained in the form of pale pink crystals with m.p. 137°-139° C. and Rf=0.47 on thin-layer silica gel plates in the system methylene chloride/methanol (15:1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1.C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[Br:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][S:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: BrCc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ccc2c(SCc3cccc(CBr)c3)ccnc2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (3.0 g, 13.1 mmol), 1,3-bis-bromomethyl-benzene (10.4 g, 39.3 mmol) and CHCl3 (150 mL) were charged in a 250 ml round-bottomed flask equipped with a magnetic stirrer. TBABr (0.5 g, 1.5 mmol) and water (12 mL) were added and the reaction mixture was stirred for 15 h at 20° C. The reaction mixture was poured in 10 mL of H2O with K2CO3 (1.8 g, 13.1 mmol), extracted with CH2Cl2 (400 mL). The organic layer was washed with water (30 mL), brine (2×30 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. Diethyl ether (150 mL) was added and the bis-alkylated product was precipitated and filtered off. The filtrate was evaporated and the crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=99.5:0.5 to 96:4) to give after evaporation 4-(3-(bromomethyl)benzylthio)-7-(trifluoromethyl)quinoline 28 (3.3 g, 61% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])([CH3:5])[C:3]#[CH:4].CO.O.Cl>O1CCCC1>[CH3:5][C:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)Oc1cccc(C(=O)OC)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(C)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.7 %

Procedure:
To a solution of methyl 3-[(1,1-dimethylprop-2-yn-1-yl)oxy]benzoate (4.0 g, 18.3 mmol) in tetrahydrofuran (10 mL) were added lithium hydroxide•monohydrate (865 mg, 20.6 mmol), methanol (10 mL) and water (5 mL), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid, and extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.8 g, 99%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[F:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:37]6[CH:38]=[N:39][C:34]([F:33])=[CH:35][CH:36]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: OB(O)c1ccc(F)nc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccc(F)nc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Yield: 65 %

Procedure:
(11β,16α,17β)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 6-fluoro-3-pyridinylboronic acid were used as described in example 1 step h. Purification by LCMS followed by lyophilisation gave the product (65% yield). 1H NMR (400 MHz, CDCl3): δ 0.34 (s, 3H), 0.80-2.85 (m, 24H), 4.45 (d, J=7 Hz, 1H), 5.80 (s, 1H), 7.00 (dd, J=8 and 3 Hz, 1H), 7.25-7.29 (m, 2H), 7.44-7.48 (m, 2H), 7.95 (dt, J=8 and 3 Hz, 1H), 8.41 (d, J=3 Hz, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:25]([CH2:27][NH2:28])[OH:26]>CN(P(N(C)C)(N(C)C)=O)C>[OH:26][CH2:25][CH2:27][NH-:28].[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Agent: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=S(Cl)Cl
Product: [NH-]CCO
Reaction time: 2 h

Procedure:
2.72 g. of 2-(4-phenoxymethylphenoxy)-propionic acid is dissolved in 12 ml. of HMPA. At -10°, 0.77 ml. of thionyl chloride is added thereto, and the mixture is agitated for 2 hours at -5°. Thereafter, 2.5 ml. of ethanolamine is added and the reaction mixture is stirred overnight at 20°. The mixture is then poured on ice and worked up as usual, yielding the 2-hydroxyethylamide of 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[C:17](Cl)=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[O:15])=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[CH:9][N:8]=1.CN(C=O)C.C1COCC1>O>[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[C:17]([S:4][CH2:2][CH3:3])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[O:15])=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[CH:9][N:8]=1
Reactant: CCS
Reactant: CNc1ncc(C(F)(F)F)cc1NC(=O)c1ccc(C(F)(F)F)nc1Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc(C(F)(F)F)ccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
256 mg of ethyl mercaptan sodium salt (80%) was added to a mixture of 810 mg of 2-chloro-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 4 ml of DMF and 1 ml of THF under ice cooling, then the mixture was heated to room temperature, and stirred for 3 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane, and then dried to obtain 705 mg of 2-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 2-Ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[CH:13](OC)[CH2:14]Br.Cl>C(O)C.ClCCl>[CH:1]1([NH:7][C:8]2[S:9][CH:13]=[CH:14][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: NC(=S)NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: c1csc(NC2CCCCC2)n1
Yield: 102.6 %

Procedure:
To a suspension of 5 g (0.032 mol) of N-cyclohexyl thiourea in 50 mL of ethanol at rt was added 5.38 g (0.0318 mol) of 1,1-dimethoxy-2-bromoethane. To the reaction mixture was then added 1.25 mL of 12N HCl and the reaction mixture was heated at reflux for 12 h. The reaction mixture was then concentrated to provide an orange-brown oil which was dissolved in 50 mL of dichloromethane. The organic solution was washed twice with 1N NaOH solution (50 mL) and then with H2O. The organic fraction was dried (Na2SO4), filtered and the filtrate was concentrated to give 5.95 g of off-white solid. The residue was purified by chromatography (silica, 0 to 5% EtOAc in cyclohexane) to give the title compound. 1H NMR (CDCl3) δ 6.45 (1H, d), 5.69 (1H, d), 4.20-4.10 (1H, m), 1.99-1.55 (6H, 3 sets of m).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH2:26][OH:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S(=O)(O)[O-].[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH:26]=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(CO)[nH]c2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: ClCCl
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C=O)[nH]c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To the solution of Example 276 (1.0 g, 2.2 mmol) in dichloromethane (50 mL) at 0° C. was added Dess-MartinPeriodinane (1.84 g, 4.34 mmol) and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then stirred at ambient temperature for three hours. A solution of sodium bisulfite (0.9 g, 9 mmol) in saturated aqueous sodium bicarbonate (5 mL) was added, and the reaction mixture was stirred for 15 minutes and extracted with ethyl acetate. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated to provide the title compound (0.80 g, 70% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc23)CC1
Yield: 58.3 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 18.0 mg (0.09 mMol) 4-(methanesulfonyl)benzoic acid, 7.2 mg of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: O=C(Nc1ccc(F)c(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
6-Chloro-7-(4-(6-(4-chlorophenyl)-5-fluoropyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylic acid (16.1 mg, 0.0291 mmol) was dissolved in MeOH-THF (0.5 mL-0.5 mL) and 0.5 M sodium methoxide solution in methanol (58.19 μl, 0.0291 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and concentrated. The residue was chased with dichloromethane multiple times and dried under high vacuum to provide 17.0 mg of the title compound as white solid (101.6%). MS (apci) m/z=553.0 (M+2H—Na).
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10]C)=[O:8])[CH:5]=[CH:4][N:3]=[N:2]1.[CH2:12](N(CC)CC)C>CO>[N:1]1([C:6](=[CH2:12])[C:7]([O:9][CH3:10])=[O:8])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cn1ccnn1
Solvent: CO
Product: C=C(C(=O)OC)n1ccnn1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
450 g of ethyl 2-(1H-1,2,3-triazol-1-yl)acetate were dissolved in 3.5 1 of methanol, 30 g of triethylamine were added and the mixture was stirred at 22° C. for 16 h. All solvents were then distilled off under reduced pressure. This gave 410 g of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[N:4]=[N:3]1.P(Br)(Br)[Br:16]>ClCCl>[Br:16][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: BrP(Br)Br
Reactant: Cn1cc(-c2ccc(CO)cc2)nn1
Solvent: ClCCl
Product: Cn1cc(-c2ccc(CBr)cc2)nn1
Temperature: 20 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a solution of [4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]methanol (3.40 g) in dichloromethane (130 mL) was added dropwise phosphorus tribromide (23.0 g) under ice-cooling, and the mixture was stirred at 20° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (×3). The combined organic layers were washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.50 g) as a mixture with phosphine oxide. This mixture was diluted with tert-butyl methyl ether, and the mixture was stirred at 20° C. for 16 hr. The precipitate was collected by filtration, and dried under reduced pressure to give the title compound (3.40 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[OH:11][CH:8]([CH2:7][O:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(O)COc1nccs1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(O)COc1nccs1
Reaction time: 0.17 h

Procedure:
This example illustrates steps 3 and 4 of the generic process, of the invention, and further illustrates the preparation of the compounds of formula II of the invention. In this example 50 grams of 3-(thiazol-2-oxy)-1,2-propanediol is dissolved in 200 ml. of pyridine at 20°C and then 22.5 ml. of methylsulfonyl chloride is added. The mixture is allowed to stand for 10 minutes and then separated into two portions (1/10 portion and one 9/10 portion). The 1/10 portion is diluted with water, then filtered and the resulting filter cake dried affording 2-hydroxy-1-methylsulfonyloxy-3-(thiazol-2-oxy)-propane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([NH:7][CH2:8][CH2:9][N:10]([C:20]1[N:25]=[C:24]([N:26]([CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][CH2:43][OH:44])=[O:40])[CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[O:31])[N:23]=[C:22](Cl)[N:21]=1)[CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[O:6].[C:46](=[O:49])([OH:48])[O-].[Na+]>C(O)CO>[OH:1][CH2:2][CH2:3][O:4][C:5]([NH:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])[C:20]1[N:25]=[C:24]([N:26]([CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][CH2:43][OH:44])=[O:40])[CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[O:31])[N:23]=[C:22]([N:10]([CH2:9][CH2:8][NH:7][C:5]([O:4][CH2:3][CH2:2][OH:1])=[O:6])[CH2:11][CH2:12][NH:13][C:46]([O:48][CH2:18][CH2:17][OH:16])=[O:49])[N:21]=1)=[O:6]
Reactant: O=C(NCCN(CCNC(=O)OCCO)c1nc(Cl)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: O=C(NCCN(CCNC(=O)OCCO)c1nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Temperature: 115 °C

Procedure:
To 6.7 g of (I) (Example 1, TECT) were added 2.8 g HEC, 0.84 g sodium bicarbonate and 25 g ethylene glycol. The reaction mixture was then heated to 115° C. in an oil bath for 4 hours, after which most of the HEC had reacted with TECT as indicated by amine titration of the reaction mixture. Ethyelene glycol was distilled off under reduced pressure. The residue was poured into methanol. Separated solids were filtered and recrystallized from methanol. Yield 5.6 g (60% of theoretical), m.p. 192° C. The nmr and fab mass spectra confirmed the product to be of FORMULA II: ##STR18##