Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]1[CH2:22][CH2:21][CH:20]2[CH:15]([CH2:16][CH:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]2)[CH2:14]1.C(OCC)C>C(Cl)Cl>[O:12]=[C:13]1[CH2:22][CH2:21][CH:20]2[CH:15]([CH2:16][CH:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]2)[CH2:14]1
Reactant: CCOC(=O)C1CC2CC(O)CCC2CN1C(=O)OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A mixture of 146.1 g of pyridinium chlorochromate, 146.1 g of powdered 4 Å sieves, and 1000 ml of methylene chloride was stirred for 1 hour at room temperature. A solution of 87.9 g of ethyl decahydro6-hydroxy-2-methoxycarbonyl-3-isoquinolinecarboxylate in 30 ml of methylene chloride was added dropwise in 200 ml of dichloromethane and the reaction mixture stirred for three hours at room temperature. Diethyl ether (1400 ml) was added to the mixture which was then filtered through a Celite® pad and silica gel pad. The filtrate was concentrated in vacuo, redissolved in diethyl ether, and again filtered through Celite and silica gel. Concentration of the filtrate afforded 78.4 g of the desired title product as a 28:72 mixture of equitorial: axial ester isomers. The residue was dissolved in 600 ml of ethanol, 1.11 g of sodium hydride dissolved in 60 ml of ethanol was added, and the mixture heated at 80° C. for 2.25 hours. The mixture was cooled and concentrated in vacuo. To the residue were added 700 ml of 1:1 dichloromethane/diethyl ether and this solution was washed with 300 ml of 10% aqueous sodium bisulfate. The organic layer was separated and the aqueous layer extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was filtered through silica gel with 40% ethyl acetate in hexane, and the filtrate was concentrated in vacuo to afford an oil. Crystallization from ether/hexane afforded 32.3 g of the desired subtitled intermediate, m.p. 79°-80° C., that was one compound by as determined by gas chromatography. By 1H NMR and X-ray crystallographic analysis, this ketone was determined to be ethyl 1a-R*-3-R*-4a-R*-decahydro-6-oxo-2-methoxycarbonyl-3-isoquinolinecarboxylate. It is assumed that this stereochemistry carries forward to each of the final products.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([CH2:14][OH:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Na+]>Cl.O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([CH2:14][OH:15])=[C:8]([C:10]([F:12])([F:11])[F:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(F)(F)F)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C(F)(F)F)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 76.9 %

Procedure:
A solution of 4.06 g of 2-butyl-5-hydroxymethyl-4-trifluoromethyl-1-[(2'-(triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]imidazole in 40 mL of 10% hydrochloric acid and 80 mL of tetrahydrofuran was stirred at 25° for 2 hours and then poured into water containing an excess of sodium hydroxide. The aqueous solution was washed with diethyl ether, adjusted to pH 3 with 10% hydrochloric acid, and then extracted with chloroform. The combined chloroform extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (elution: 10% methanol/chloroform) furnished 2.04 g of 2-butyl-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-4-trifluoromethylimidazole as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@@H:22]([CH3:40])[CH2:23][N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([C:27]4[CH2:28][CH2:29][N:24]([CH2:23][C@@H:22]([OH:21])[CH3:40])[CH2:25][CH:26]=4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(C2=CCN(C[C@H](C)O)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(C2=CCN(C[C@H](C)O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 44 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4[1-((S)-2-hydroxypropyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2-methoxybenzaldehyde were reacted to produce the title compound (44%). 1H NMR (d-4 methanol): 8.26 (d, J=7 Hz, 1H), 7.94 (s, 1H), 7.24 (m, 2H), 6.42 (m, 2H), 6.31 (s, 1H), 5.33 (m, 1H), 4.29 (m, 1H), 4.11 (s, 3H), 4.07 (m, 2H), 3.65 (m, 2H), 3.39-3.27 (m, 6H), 3.17 (m, 1H), 3.07-2.85 (m, 4H), 2.77 (d, J=7 Hz, 1H), 2.34 (d, J=7 Hz, 1H), 1.57 (d, J=7 Hz, 1H), 1.56 (d, J=7 Hz, 1H), 1.30 (d, J=7 Hz, 3H). MS: 549.19 (M+H). HPLC retention time: 1.86 minutes (G Method).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:19]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=[N:1][C:2]=12)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCC(=O)Nc1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1

Procedure:
A solution of 1.87 g of 3-amino-4-benzoylpyrazole and 2.46 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide (Example 169) in 50 ml of glacial acetic acid was refluxed for 15 hours and then evaporated to yield a pale yellow gum. This material was partitioned between an aqueous saturated sodium bicarbonate solution and methylene chloride. The methylene chloride solution was dried with powdered anhydrous sodium sulfate and then passed through a short column of hydrous magnesium silicate adsorbent. The eluate was refluxed in a steam bath and hexane gradually added until turbidity. After cooling, the desired product was recovered by filtration (2.39 g, mp 172°-174° C.).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[O:28][CH2:29][CH2:30][OH:31])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[O:28][CH2:29][CH2:30][O:31][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:35][CH:36]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CI
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCO)c3)cc2)cccc1[N+](=O)[O-]
Product: CCOC(=O)COCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 92B and ethyl iodoacetate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[O:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]1[CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>CO>[ClH:1].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH2:30][CH:18]2[CH2:19][NH:20][CH2:21][CH2:22][N:17]2[C:9]2[O:8][C:16]3[C:11]([N:10]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ncccc3o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1cncc(OCC2CNCCN2c2nc3ncccc3o2)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(oxazolo[4,5-b]pyridin-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (273 mg, 0.664 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were combined and brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.116 mL) was added. The mixture was concentrated under reduced pressure to give 148 mg (64%) of the desired product as the hydrochloride salt. LC-MS: RT=2.18 min, [M+H]+=312.5.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pt]=O.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccccc1N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Yield: 58 %

Procedure:
A mixture of 5.00 g (0.0142 m) of 1-[(p-nitrophenyl)sulfonyl]-4-(o-methylphenyl)piperazine, 0.3 g of platinum oxide, and 150 ml of chloroform is shaken under pressure on a Parr hydrogenator until hydrogen uptake ceases (25 minutes). The catalyst is removed on a fine sintered glass funnel and the filtrate is taken to dryness. Crystallization from ethyl acetate/methylene chloride/Skellysolve® B hexanes gives 2.66 g (57%) of 1-[(p-aminophenyl)-sulfonyl]-4-(o-methylphenyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH:15]=[C:14]([Br:23])[CH:13]=[CH:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Yield: 67.8 %

Procedure:
Ethyl 2-amino-1-benzothiophene-3-carboxylate (10.4 g, 44.7 mmol) was dissolved in chloroform (100 mL) and treated with NBS (7.95 g, 44.7 mmol). Upon completion of the reaction, a light tan solid precipitated from the mixture. The slurry was concentrated to ˜30% of the original volume on a rotavap and then filtered. The solid was slurried in EtOAc (300 mL) and treated with satd NaHCO3 (200 mL) to obtain two clear phases. The organic phase was washed further with satd NaHCO3 (4X˜200 mL) and water (200 mL). The organic layer was collected, dried with sodium sulfate, filtered, and concentrated to yield an off-white solid (9.1 g, 68%). 1H NMR (DMSO-d6) δ 8.00 (s, 2H), 7.85 (s, 1H), 7.83 (d, 1H), 7.36 (d, 1H), 4.28 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:13][N:12]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[C:9]2=[CH:10][CH:11]=1)C.O[Li].O>C1COCC1.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([C:8]3[C:9](=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:37])=[O:3])[CH:7]=3)[N:12]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:13]2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CC(=O)O)ccc43)c21

Procedure:
A solution of (R)-tert-butyl 5-(2-ethoxy-2-oxoethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.325 g, 0.641 mmol) in THF:H2O (2:1, 3 mL) was treated with LiOH—H2O (0.067 g, 1.6 mmol) at about 0° C. The reaction was stirred with warming to about room temperature overnight. The reaction was concentrated and diluted with EtOAc. The organic was washed with saturated NaHCO3, acidified with 1N HCl, and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to yield (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid. LCMS (APCI+) m/z 479.3 [M+H]+; Rt=2.82 min.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH3:8])=[CH:5][C:6]=1[CH3:7].[C:9](Cl)(=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:9]([C:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[S:3][C:4]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: Cc1cc(C)c(Cl)s1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(C)sc(Cl)c1C
Temperature: 0 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
To a stirred solution of 2-chloro-3,5-dimethylthiophene (0.9 g, 6.18 mmol) in petroleum ether (5 mL) was added acetyl chloride (0.9 mL, 12.4 mmol) and aluminum chloride (0.99 g, 7.42 mmol) at room temperature under nitrogen, and the mixture stirred for 1 day. The reaction mixture was poured into ice water (50 mL) and the whole was extracted with diethyl ether (70 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (20:1) to provide the title product (0.85 g, 73% yield).
Reaction SMILES: C(O/[CH:4]=[C:5](\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)/[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.Cl.[NH2:21]O>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:4]=[N:21][O:12][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:14][CH:15]=1
Reactant: CCO/C=C(/C(=O)C(=O)OCC)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1oncc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of (E)-ethyl 4-ethoxy-3-(4-fluorophenyl)-2-oxobut-3-enoate (1.5 g, 5.63 mmol, 1.00 equiv) and hydroxylamine hydrochloride (2 g, 28.99 mmol, 5.15 equiv) in ethanol (10 mL) was refluxed for 3 h. The reaction mixture was cooled to room temperature and then quenched by 15 mL of saturated sodium bicarbonate solution. The resulting mixture was extracted with 2×10 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to yield 340 mg (26%) of ethyl 4-(4-fluorophenyl)-1,2-oxazole-5-carboxylate as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.57 (s, 1H), 7.47-7.43 (m, 2H), 7.11-7.03 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Fc1cnc(Cl)nc1Nc1ccc(C(F)(F)F)cc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 2.1 Hz), 7.80 (d, 2H, J=7.1 Hz), 7.66 (d, 2H, J=9 Hz), 7.10 (bs, 1H); 19F NMR (CDCl3): −17682 and −44362; LCMS: purity: 91% and MS (m/z): 292 (MH+).
Reaction SMILES: [F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].O.C([O-])([O-])=O.[K+].[K+]>CO.[Pd]>[CH2:16]([C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:27]([F:38])=[CH:28][CH:29]=[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])[C:2]=3[F:1])[CH:8]=2)[NH:13][CH:14]=1)[CH3:17]
Reactant: C=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(CC)c3c2)c1F
Reaction time: 1 h
Yield: 37.6 %

Procedure:
2,6-Difluoro-N-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0093 g, 0.017 mmol) was dissolved in MeOH (1.0 mL). 10% Pd/C (2.0 mg) was added and followed by stirring under a balloon of H2 for 1 hour. Water (0.3 mL) and K2CO3 (0.0235 g, 0.170 mmol) were added, and the reaction mixture was stirred at 50° C. for 18 hours. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (1:2 hexane/EtOAc) giving N-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (2.7 mg, 37.6%). 1H NMR (400 MHz, DMSO-d6) δ 11.33 (br s, 1H), 10.84 (s, 1H), 9.79 (br s, 1H), 8.32-8.34 (m, 2H), 7.51-7.57 (m, 1H), 7.24-7.27 (m, 2H), 3.10-3.14 (m, 2H), 2.67-2.73 (m, 2H), 1.74-1.80 (m, 2H), 1.25-1.28 (m, 2H), 0.98-1.01 (m, 3H); m/z (APCI-neg) M−1=421.2.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][S:10](=[O:12])(=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[OH-:13].[Na+:14]>O>[Na+:14].[S:10]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([O-:13])=[O:8])([OH:9])(=[O:12])=[O:11]
Reactant: [OH-]
Reactant: O=C1OS(=O)(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1ccccc1S(=O)(=O)O

Procedure:
20 g (108.6 mmoles) of 2-sulfobenzoic acid cyclic anhydride were added to a beaker containing 250 mL of water. After the reactant dissolved, 4.4 g (110 mmoles) of sodium hydroxide were added. After the water was removed, 22.9 g (94% of theory) of a white powder product, I-32, the title compound, were recovered.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH2:24]([OH:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CCCCOc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with n-butanol according to the procedure described in Example 59 to afford 2-(n-butyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=407 (M++1); Rt=4.80 min; 1H-NMR 400 MHz (CDCl3): δ 1.00 (t, 3H), 1.50-1.6 (m,2H), 1.80-1.85 (m, 2H), 4.41-4.44 (t, 2H), 7.01 (d, J=9 Hz, 2H), 7.21-7.25 (m, 5H), 8.58 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][CH2:16][O:15][CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[CH:22]=2)=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
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: C1COCCO1
Product: Fc1ccc(-c2cnn(CCOC3CCCCO3)c2)cn1
Temperature: 85 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (176 mg, 1.00 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (322 mg, 1.00 mmol), Pd(PPh3)4 (115 mg, 0.100 mmol) and Na2CO3 (212 mg, 2.00 mmol) in 1,4-dioxane (5 ml) was bubbled with N2 for 10 min and then stirred at 85° C. for 6 h. After being cooled to rt, the reaction mixture was filtered through celite and the filtrate was diluted with EA. The organic phase was washed with water, brine and dried over anhydrous MgSO4. Filtered and concentrated to afford the title compound (0.206 g, yield 63.6%), which was used in next step without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.48 (s, 1H), 8.27 (s, 1H), 8.17 (dd, 1H), 7.98 (s, 1H), 7.19 (d, 1H), 4.53 (s, 1H), 4.30 (t, 2H), 3.95 (m, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 3.35 (t, 1H), 1.65 (m, 1H), 1.57 (m, 1H), 1.40 (m, 4H). LCMS (method B): [M+H]+=292, tR=2.16 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1([CH3:36])[OH:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1([OH:35])[CH3:36])=[O:11]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: CC1(O)CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)NC2CCCCC2(C)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (100 mg, 0.358 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (250 μl, 3.41 mmol) was added followed by 2-amino-1-methylcyclohexanol hydrochloride (65 mg, 0.39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (205 mg, 1.07 mmol) and 1-hydroxybenzotriazole (53 mg, 0.39 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution and diethyl ether. The organic was washed with sat. sodium bicarbonate solution, water and brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (5:95 to 50:50) as eluant to give 5-fluoro-N-(2-hydroxy-2-methylcyclohexyl)-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a white solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:25][CH2:26][CH2:27][OH:28])[S:23][CH:24]=2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([N:25]3[CH2:26][CH2:27][O:28][C:1]3=[O:2])[S:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCCNc1nc(-c2ccc(Cl)cc2)cs1
Solvent: C1CCOC1
Product: O=C1OCCN1c1nc(-c2ccc(Cl)cc2)cs1
Reaction time: 72 h
Yield: 6 %

Procedure:
1,1′-Carbonyldiimidazole (0.16 g, 1 mmol) was added to a solution of 2-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}ethanol (0.15 g, 0.58 mmol), prepared in the previous step, in dry tetrahydrofuran (5 mL) at room temperature under nitrogen. After 72 h, the mixture was evaporated and the residue purified by silica gel column chromatography (ethyl acetate:hexanes, 1:3 as eluant) to afford the title compound (9.8 mg, 5%) as a white solid, MS (ES) m/z 281 [M+H]+. ANLC 96.4%@210 nm, 96.2%@230 nm; RT=8.0 min, the Xterra® MS C18m instrument, 3.5μ, 4.6×50 mm column, 0.8 mL/min, Grad: 5/95-95/5 (A) the PIC™ B6 reagent (5 mM Hex. Sulfonic Acid); (B) AcCN.