Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([S+:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26].Br[CH2:32][C:33](=[CH2:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(#N)C>[C:16]1([S+:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[C:37]([O:36][C:34]([C:33](=[CH2:32])[CH2:41][O:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Reactant: O=S(=O)(O)C(F)(F)CO
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C=C(COCC(F)(F)S(=O)(=O)O)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 61 %

Procedure:
In a 100-ml flask, 31 g of an aqueous solution of 5 mass % sodium hydroxide was placed. The solution was cooled, with stirring, by immersing the flask in an ice water bath. Then, 15.0 g of 2-hydroxy-1,1-difluoroethanesulfonic acid triphenylsulfonium (purity: 95%, 0.035 mol) was gradually added to the solution. The solution was returned to room temperature and stirred for 30 minutes. The solution was again cooled by immersing the flask in the ice water bath. After that, a solution of 6.5 g of tert-butyl 2-bromomethylacrylate (0.029 mol) in 10 g of acetonitrile was dropped into the above solution. The mixed solution was further stirred for 1.5 hours at room temperature. The thus-obtained reaction solution was separated into upper and lower layers. The lower layer was mixed with 20 g of chloroform and washed three times with 24 g of water. The resulting solution was solidified by concentration under reduced pressure. The solid product was dissolved in 10 g of methyl ethyl ketone at 40° C. Into the product solution, 25 g of diisopropyl ether was slowly dropped. The product solution was then stirred for 1 hour at room temperature. After confirming the deposition of a crystalline substance, the crystalline substance was filtered out and dried under reduced pressure. With this, 10 g of the target compound (PAG-1) was obtained as a white solid substance (purity: 99%, yield: 88%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Cl.CN(C)CCCN=C=NCC.[CH:37](O)=[O:38]>O1CCCC1.C(Cl)Cl>[CH:37]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:38]
Reactant: O=CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-3-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (171 mg) and formic acid (34 μL) in dry tetrahydrofuran (6 mL) is stirred at ambient temperature for one hour, diluted with methylene chloride (10 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 186-187° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)(=[O:4])=[O:3].[OH-].[K+].[I:16]I.O>CS(C)=O>[I:16][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[NH:10][N:9]=1
Reactant: CS(=O)(=O)c1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a solution of 5-(methylsulfonyl)-1H-indazole (430 mg, 2.19 mmol) in DMSO (10 mL) at 0° C., were added KOH (0.4 g, 6.57 mmol) and I2 (1.2 g, 4.38 mmol) successively, then the reaction mixture was stirred at room temperature for 3 hours. Water (40 mL) was added, product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=20:1) to give 3-iodo-5-(methylsulfonyl)-1H-indazole (410 mg, 59.9%) as an off-white solid. LCMS: (M+H)+=323; 1H NMR (300 MHz, DMSO): δ 7.98-7.95 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@@H:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][C@H:21]2[OH:27])=[C:15]([N+:28]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:57](OC2C=CC=CC=2)=[N:58][C:59]#[N:60])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@@H:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][C@H:21]3[OH:27])/[C:57](=[N:58]/[C:59]#[N:60])/[NH:28][C:15]=2[CH:14]=1
Reactant: CN1CC[C@@H](Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])[C@H](O)C1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1CC[C@@H](n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Dissolve (3R,4R)-4-[4-((E)-3,7-Difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenylamino]-1-methyl-piperidin-3-ol (0.009 mol, 4.48 g) in tetrahydrofuran (100 mL). Add triethylamine (0.018 mol, 1.83 g) and 10% platinum on carbon (2.2 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 4 h. Filter off the catalyst through a plug of diatomaceous earth. Add pyridine (100 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.16 g) to the filtrate. Stir at room temperature for 16 h and then heat at 60-70° C. for 8 h. Remove the solvent under reduced pressure. Dissolve the residue in dichloromethane and wash with water and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to obtain the title compound (1.2 g, 26%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.66-1.8 (m, 1H), 1.75-1.78 (m, 1H), 1.87-1.90 (m, 1H), 2.03 (br s, 1H), 2.24 (s, 3H), 2.81 (br s, 1H), 2.96 (br s, 1H), 3.99 (br s, 1H), 4.31 (br s, 1H), 5.09 (s, 1H), 5.36 (br s, 1H), 5.46 (br s, 1H), 6.68 (dd, 1H), 6.82-6.87 (m, 3H), 6.99 (d, 1H), 7.09 (s, 1H), 7.26-7.35 (m, 3H), 7.62 (t, 1H), 12.49 (br s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([O:56][C:57]1[CH:62]=[C:61](Cl)[N:60]=[C:59]([S:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[C:67]=2[F:73])[N:58]=1)[CH3:55])[CH3:51]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([O:56][C:57]1[CH:62]=[C:61]([NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:8])=[O:7])[N:60]=[C:59]([S:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[C:67]=2[F:73])[N:58]=1)[CH3:55])[CH3:51]
Reactant: NS(=O)(=O)c1nccs1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2nccs2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 2-thiazolesulfonamide (0.17 g), tris(dibenzylideneacetone)dipalladium (0) (64 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (33 mg), cesium carbonate (0.34 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (0.27 g) in dioxane (5 mL). Purification was by column chromatography on silica using EtOAc/isohexane (1:9 to 1:1 gradient) as eluent to give the subtitle compound as a pale yellow oil. Yield: 0.11 g
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)cc1OC
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,4-dimethoxyaniline were reacted to yield N2-(3,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.98 min.; purity: 74%; MS (m/e): 399 (MH|).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2.[OH-].[K+]>CO.O>[O:4]=[C:5]1[CH2:3][CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2
Reactant: C=[N+]=[N-]
Reactant: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of diazomethane (Diazald, 2.70 g) in MeOH (15 mL) was added dropwise to a mixture of ketone 1A (997 mg) and KOH (3.81 g) in MeOH (10 mL) and water (1.8 mL) at 0° C. over a period of 1.5 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The resulting suspension was concentrated and was diluted with water (50 mL). The resulting aqueous suspension was extracted with ether (1×), then with DCM (2×), and the combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0/100 to 10/90 MeOH/EtOAc) to provide 964 mg of ketone 8A as a white solid. Data: LC/MS (ESR) m/z 222 [M+1]+, 244 [M+Na]+.
Reaction SMILES: NOS(O)(=O)=O.CC(C)([O-])C.[K+].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].C[N:37]1CCCC1=O.NOS(O)(=O)=O.CN1CCCC1=O>CN1CCCC1=O>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH2:37])[CH:25]=[CH:24]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Product: Nn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 2.77 h
Yield: 953.5 %

Procedure:
A solution of 5.3 kg (5.2 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 19.1 kg of N-methylpyrrolidinone (NMP), is prepared and chilled to 0–5° C. A second solution is prepared from 10.6 kg (10.0 kg corrected for 95% purity) of potassium tert-butoxide and 19.3 kg of NMP. An amination vessel is charged with 5.0 kg (4.7 kg corrected for 94% purity) of 5-benzyloxyindole, 15.5 kg of NMP and an initial charge of 0.4 kg of the potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered into the amination vessel over a period of 166 minutes while maintaining a reaction temperature of 14–29° C. to yield a solution containing 4.3 kg (86.0% yield) of 5-benzyloxy-1H-indol-1-amine as determined by external standard HPLC assay. After adding 105 L water, and cooling to 0–5° C., the mixture is filtered. The filtered solid is partitioned with 63 L n-butyl acetate and 8.5 L water, then filtered. The organic phase is concentrated under reduced pressure to give a solid which contains 3.9 kg (77.4% yield) of 5-benzyloxy-1H-indol-1-amine as determined by external standard HPLC assay.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([SiH](CC)CC)C.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[Cl:27][CH2:28][CH2:29][C:30]([C:13]1[CH:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1)=[O:31]
Reactant: CCCCCCCC(=O)c1ccccc1
Reactant: O=C(Cl)CCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCc1ccc(C(=O)CCCl)cc1
Temperature: 5 °C

Procedure:
Octanophenone (50 g), dichloromethane (250 mL), and triethylsilane (69.77 g) are charged into a round bottom flask, stirred, and cooled to 0-10° C. Titanium tetrachloride (55.7 g) in dichloromethane (250 mL) is added to the reaction mixture over 30-35 minutes at temperature below 10° C. and the reaction mixture is stirred at a temperature of 25-30° C. for about 1 hour. The reaction mixture is filtered through a hyflo bed and washed with dichloromethane (100 mL). The filtrate obtained is charged into a second round bottom flask, aluminium chloride (41.6 g) is added, and the reaction mixture is cooled to 0-5° C. 3-Chloropropionyl chloride (30.47 g) in dichloromethane (50 mL) is added slowly to the reaction mixture at temperature below 5° C. and the reaction mixture is allowed to a temperature of 25-30° C. and maintained at the same temperature for about 1 hour. The reaction mixture is slowly added to water (500 mL) precooled to 0° C. and stirred. The organic layer is separated, washed with aqueous sodium bicarbonate solution (2×500 mL), water (500 mL), followed by brine solution (100 mL), dried over sodium sulphate and concentrated under reduced pressure at a temperature of about 45° C. to obtain 3-chloro-1-(4-octylphenyl)propan-1-one.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:21]=[C:20]2[C:10]([NH:11][CH:12]=[C:13]2[CH2:14][CH:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:9][CH:8]=1.[CH3:22]O>>[CH3:22][O:18][C:17](=[O:19])[CH:15]([CH2:14][C:13]1[C:20]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH3:5])[CH:21]=2)[NH:11][CH:12]=1)[NH2:16]
Reactant: CO
Reactant: COc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
Thionyl chloride (1.0 mL, 13.7 mmol) was added dropwise to a slurry of 5-methoxy-DL-tryptophan (2.0 g, 8.54 mmol) in anhydrous methanol (22 mL) at 0° C. under a nitrogen blanket. The resulting solution was warmed slowly to room temperature, stirred for 17 hours, then the solvent was removed under reduced pressure. The resulting residue was dissolved in water (20 mL), neutralized with saturated NaHCO3 (10 mL), and extracted twice with methylene chloride. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to provide 5-methoxy-DL-tryptophan methyl ester (Intermediate 4) as a light brown solid (1.55 g, 73%): 1H NMR (300 MHz, CDCl3): δ 7.93 (bs, 1H), 7.30-7.25 (m, 1H), 7.09-7.03 (m, 1H), 6.90-6.83 (m, 1H), 3.90-3.78 (m, 4H), 3.72 (s, 3H), 3.30-3.20 (m, 1H), 3.10-2.98 (m, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=3[N:12]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[O:33])=[C:26]([CH3:40])[CH:25]=3)=[O:23])[CH2:11][C:10]=2[CH:9]=[N:8]1>ClCCl.C(N(CC)CC)C>[CH3:6][N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=3[N:12]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:39][CH2:38][N:37]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:36][CH2:35]4)=[O:33])=[C:26]([CH3:40])[CH:25]=3)=[O:23])[CH2:11][C:10]=2[CH:9]=[N:8]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CCC(=O)N2CCNCC2)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CCC(=O)N2CCN(S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.36 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=551.3
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O:20]CC)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:24]>C(O)C>[O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:24]
Reactant: CCOC(=O)c1nc2ccccn2c1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1nc2ccccn2c1COc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (889 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The precipitated crystals were collected by filtration, and washed with ethanol to give sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (680 g). The obtained sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (290 mg), tert-butyl(3S, 5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μ) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (563 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A 2 L flask was charged with 5-bromo-3-phenoxypyridin-2-amine (64.0 g, 241.4 mmol) and benzoyl isothiocyanate (35.82 mL, 265.6 mmol) in THF (600 mL) and stirred at ambient temperature overnight, then concentrated to about 50 mL. A mixture of Hexanes:EtOAc (9:1) (900 mL) was added with vigorous stirring. The resulting suspension was filtered and the solid was washed with hexanes then dried to afford 1-benzoyl-3-(5-bromo-3-phenoxypyridin-2-yl)thiourea (94.32 g, 91.2% yield) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:6]([CH2:9][O:10][CH3:11])=[CH:7][CH:8]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:11][O:10][CH2:9][C:6]1[N:5]2[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:4]2[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1
Reactant: COCc1ccc(CO)c2cc(C(F)(F)F)nn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COCc1ccc(C=O)c2cc(C(F)(F)F)nn12
Temperature: 50 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
Activated manganese dioxide (20.0 g) was added to a solution of the compound of Example 326 (6.00 g) in chloroform (120 mL). The reaction mixture was stirred at 50° C. for 5 hours. Subsequently, the mixture was filtered through Celite. The filtrate was concentrated to afford the title compound as a pale yellow powder (5.74 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10](=[O:30])[NH:11][C:12]1[S:13][C:14]([CH3:29])=[C:15]([CH:26]2[CH2:28][CH2:27]2)[C:16]=1[C:17]1[O:21][N:20]=[C:19]([C:22]([F:25])([F:24])[F:23])[N:18]=1)=[O:4].O.Cl.CCOC(C)=O>O1CCOCC1>[CH:26]1([C:15]2[C:16]([C:17]3[O:21][N:20]=[C:19]([C:22]([F:23])([F:24])[F:25])[N:18]=3)=[C:12]([NH:11][C:10]([C:6]3[CH2:7][CH2:8][CH2:9][C:5]=3[C:3]([OH:4])=[O:2])=[O:30])[S:13][C:14]=2[CH3:29])[CH2:27][CH2:28]1
Reactant: COC(=O)C1=C(C(=O)Nc2sc(C)c(C3CC3)c2-c2nc(C(F)(F)F)no2)CCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1sc(NC(=O)C2=C(C(=O)O)CCC2)c(-c2nc(C(F)(F)F)no2)c1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-cyclopropyl-5-methyl-3-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-thiophen-2-ylcarbamoyl]-cyclopent-1-enecarboxylic acid methyl ester (80 mg, 181 μmol, intermediate 7) in dioxane (3 mL) was added H2O (3 mL) and LiOH monohydrate (9.51 mg, 227 μmol) and the resulting clear solution was stirred at RT for 8 h. The reaction mixture was poured on 100 mL 1M aqueous HCl and 100 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 100 mL EtOAc. The organic layers were washed with 100 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 80:20). Yellow solid (57 mg, 74%). MS (ESI): m/z=428.088 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=3[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)COc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Yield: 79.1 %

Procedure:
By the method of Example 1, Step I, 2.0 g (0.0077 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 3.53 g (0.0151 mole) of methyl (2-chloromethyl-5-methylphenoxy)acetate were reacted in the presence of 1.60 g (0.0116 mole) of anhydrous potassium carbonate in 40 mL of N,N-dimethylformamide, yielding 2.75 g of methyl [2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]acetate. The NMR spectrum was consistent with the proposed structure. NMR: 2.30 (s, 3H); 2.44 (s, 3H); 3.78 (s, 3H); 4.70 (s, 2H); 5.18 (s, 2H); 6.60-7.36 (m, 7H).