Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[C:5]([I:9])=[C:4]([CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:13][C:6]1[C:5]([I:9])=[C:4]([CH3:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1nc(C)c(I)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(I)c(Cl)n1
Yield: 93.5 %

Procedure:
A mixture of 2,6-dimethyl-5-iodo-4-hydroxypyrimidine (24.5 g, 0.098 mol), phosphorus oxychloride (30.0 g, 0.196 mol) and toluene (200 mL) was heated under reflux for 1 h. The mixture was concentrated and ice water (100 mL) was added. The pH was adjusted to 5 with 2.5N NaOH and the mixture was extracted with CH2Cl2. The combined extracts were washed with brine, dried MgSO4), and concentrated to give 24.6 g of a brown solid. The crude product was combined with 26.0 g of similarly prepared material and filtered through a short column of silica gel eluted with CH2Cl2 to give 33.8 g (62%) of product as a yellow solid. An analytical sample was recrystallized from hexane/CH2Cl2, mp 62°-64° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCCOc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCOc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(4-bromobutoxy)naphthlene (1.12 g). The mixture was stirred and heated under argon at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was crystallized from dichloromethane-diethyl ether to provide 1.1 g of 4-[[4-(2-naphthalenyloxy)butyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 93°-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33](O)=[O:34])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]([C:41]1([O:44][S:45](=[O:48])(=[O:47])[NH2:46])[CH2:43][CH2:42]1)=[O:40].S(=O)(=O)(O)N>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:26](=[O:36])[NH:27][C:28]1([C:33]([NH:46][S:45]([O:44][C:41]2([C:39]([O:38][CH3:37])=[O:40])[CH2:42][CH2:43]2)(=[O:48])=[O:47])=[O:34])[CH2:30][CH:29]1[CH2:31][CH3:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1(OS(N)(=O)=O)CC1
Reactant: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)O
Agent: NS(=O)(=O)O
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1(C(=O)OC)CC1

Procedure:
2-[2-Ethyl-1-(1-methoxycarbonyl-cyclopropoxysulfonylaminocarbonyl)-cyclopropylcarbamoyl]-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared according to the method presented in Example 27. Treatment of 2-(1-carboxy-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.10 mmol) occurred under the same conditions, adjusted for scale with the exception of utilizing sulfamic acid 1-sulfamoyloxy-cyclopropanecarboxylic acid methyl ester (40 mg, 60%): LCMS found 676.2 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 73.8 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 73.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH:18]([N:21]([CH:36]([CH3:38])[CH3:37])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:20])[CH3:19]>C(O)C.N1CCCCC1>[CH:36]([N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])([CH3:37])[CH3:38]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.4 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (40 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[C:39]([O:44][CH2:45][CH2:46][N:47]=[C:48]=[O:49])(=[O:43])[C:40]([CH3:42])=[CH2:41]>CS(C)=O>[C:39]([O:44][CH2:45][CH2:46][NH:47][C:48](=[O:49])[NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: CS(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
22.3 g of 2-aminoanthraquinone (manufactured by Wako Pure Chemical Industries, Ltd.) and 180 g of dimethyl sulfoxide were stirred at 60° C., and then 0.04 g of STANOCT (trade name, manufactured by API Corporation; stannous octoate) was added thereto. Furthermore, 20.2 g of KARENZ MOI (trade name, manufactured by Showa Denko Kabushiki Kaisha; 2-isocyanatoethyl methacrylate) was added thereto, and the mixture was stirred for 4 hours. The reaction solution was filtered, and the filtrated was cooled to room temperature. Subsequently, 200 g of normal hexane was added to the reaction solution, and the mixture was stirred for one hour and then was subjected to filtration and washing, to obtain 33.1 g of 2-(2-methacryloyloxyethylureido)anthraquinone. 175 g of N-methylpyrrolidone (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 21.1 g of 2-(2-methacryloyloxyethylureido)anthraquinone and 60.9 g of thioglycerol (manufactured by Sigma-Aldrich Co.), and the mixture was heated to 65° C. and stirred for 30 minutes under a nitrogen atmosphere. Subsequently, 0.14 g of V-65 (trade name, manufactured by Wako Pure Chemical Industries, Ltd.; 2,2′-azobis(2,4-dimethylvaleronitrile) was added thereto, and the mixture was stirred for 2 hours. 500 g of a mixed solvent of water/methanol (mixture at a weight ratio of 1:1) was added to the reaction solution, and the crystals crystallized out therefrom were separated by filtration and were washed using 100 g of methanol. The obtained solids were dried under reduced pressure, and 23.0 g of M-8 was obtained as brown solids.
Reaction SMILES: C([N:9]1[C:22]2[CH:21]=[CH:20][C:19]([NH:23][CH2:24][CH3:25])=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([NH:26][CH2:27][CH3:28])[CH:14]=2)(=O)C1C=CC=CC=1.C([BH-](CC)CC)C.[Li+].[OH:37][C:38]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][C:39]=1[C:51]([CH3:54])([CH3:53])[CH3:52].O>O1CCCC1>[C:51]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:38]=1[OH:37])[C:42]([N:9]1[C:22]2[CH:21]=[CH:20][C:19]([NH:23][CH2:24][CH3:25])=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([NH:26][CH2:27][CH3:28])[CH:14]=2)=[O:43])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCNc1ccc2c(c1)Oc1cc(NCC)ccc1N2C(=O)c1ccccc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)Oc1cc(NCC)ccc1N2C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h

Procedure:
A solution containing 4.29 g of 10-benzoyl-3,7-diethylaminophenoxazine in 15 ml of tetrahydrofuran was added to 26 ml of 1M lithium triethylborohydride in tetrahydrofuran. After the addition was complete, the mixture was stirred for one hour. To this was added, over 15 minutes, 3.1 grams of 4-hydroxy-3,5-di-t-butylbenzoyl chloride. The mixture was stirred for one hour. Water was added and the product extracted into ethyl acetate. The solvent was removed and the product filtered through a pad of silica gel, and eluted with 1:3 ethyl acetate-hexane. Additional chromatography over alumina and elution with 1:4 ethyl acetate-hexane followed by recrystallization from etherhexane and finally from methanol gave 0.6 gm of the color forming developer.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[S:15]([CH3:18])(=[O:17])=[O:16].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][S:15]([N:14]([CH3:13])[CH:19]1[CH2:20][CH2:21][N:22]([C:2]([Cl:1])=[O:4])[CH2:23][CH2:24]1)(=[O:16])=[O:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C1CCN(C(=O)Cl)CC1)S(C)(=O)=O
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (0.61 g, 2.08 mmol) in CH2Cl2 (30 mL) at −78° C., was added a solution of N-Methyl-N-piperidin-4-yl-methanesulfonamide (preparation described in the patent GB2000136) (1.00 g, 5.20 mmol) and pyridine (0.92 mL, 11.4 mmol) in CH2Cl2 (20 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded 0.53 g (40%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:24]([N:4]1[C:3]([CH2:1][CH3:2])=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH2:25][CH2:26][CH3:27]
Reactant: CCc1nc2ncnc(-c3c(C)cc(C)cc3C)c2[nH]1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCn1c(CC)nc2c(-c3c(C)cc(C)cc3C)ncnc21
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A solution of 8-ethyl-6-(2,4,6-trimethylphenyl)purine (200 mg, 0.75 mmol) in anhydrous dimethylfomamide (5 mL) was cooled to 0° C., and treated with sodium hydride dispersion in mineral oil (72 mg 50% w/w, 1.50 mmol). After 1 hour, bromobutane (0.10 mL, 0.90 mmol) was added by syringe, and the mixture was allowed to stir for 12 hours. It was poured into ethyl acetate (120 mL), and was washed with water (3×120 mL) and brine (100 mL). The aqueous layers were back-extracted in sequence with ethyl acetate (120 mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the title product as a viscous oil (64.2 mg, 0.20 mmol, 27%). TLC R, 0.20 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.96 (1H, s), 6.95 (2H, s), 4.25 (2H, t, J=7.5 Hz), 2.93 (2H, q, J=7.7 Hz), 2.32 (3H, s), 2.04 (6H, s), 1.91-1.86 (2H, m), 1.50-1.38 (2H, m), 1.39 (3H, t, J=7.7 Hz), 1.01 (3H, t, J=7.5 Hz). MS(NH3 -CI): m/e 325 (3), 324 (23), 323 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([CH2:25][O:26][CH3:27])([C:22]([OH:24])=O)[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:45])[NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1)=[NH:36])([CH3:31])([CH3:30])[CH3:29]>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([C:22](=[O:24])[NH:44][CH2:43][C:40]3[CH:41]=[CH:42][C:37]([C:35]([NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:45])=[NH:36])=[CH:38][CH:39]=3)([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Reactant: COCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: COCC1(C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 100 %

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 23b (57.8 mg, 0.155 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 94 mg (100%) of intermediate 23c.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]1[O:11][CH2:10]1>C(O)C.C(N(CC)CC)C>[CH2:13]([O:12][CH2:8][C@H:9]([OH:11])[CH2:10][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O[C@@H](COCc1ccccc1)COc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of phenol (3.3 g; 35 mmol), benzyl(R)-(+)-glycidyl ether (5 g; 30.5 mmol) and triethylamine (300 μl; 2.15 mmol) in absolute ethanol (80 ml) was heated to reflux and stirred for 2 hours and then cooled to 60° C. and stirred overnight. The crude reaction mixture was concentrated under reduced pressure and the residues purified by silica gel chromatography using an eluant of hexanes and ethyl acetate (85:15 v/v) to afford 5.7 g (72.5%) of the pure product. m/z (ES) 281.1 (M+Na)+.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])=[CH:5][C:4]1=[O:31].[C:32]([O:36][P:37]([O:44][K])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[P:37]([O:44][CH2:2][N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])=[CH:5][C:4]1=[O:31])([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38]
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1
Reactant: CC(C)(C)OP(=O)(O[K])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
The crude N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide from the previous step was taken up in N,N-dimethylformamide (5 mL). Di-tert-butoxyphosphoryloxypotassium (496.6 mg, 2.0 mmol) and tetrabutylammonium iodide (36.94 mg, 0.10 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate and washed with water then brine, dried with Na2SO4, filtered and evaporated to dryness. The material was purified by column chromatography (40 g silica, 50-100% EtOAc in Hexanes), fractions with the product were pooled and evaporated to give di-tert-butyl [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (20) (280 mg, 45%) as a yellow oil that was used in the next step without further purification. ESI-MS m/z calc. 628.20, found 629 (M+1)+; Retention time: 0.76 minutes (1 minute run).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][CH:18]1[CH:23]([OH:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][S:29][C:19]1=2>ClCCl>[C:1]([NH:17][CH:18]1[CH:23]([OH:24])[C:22]([CH3:25])([CH3:26])[O:21][C:20]2[CH:27]=[CH:28][S:29][C:19]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2ccsc2C(N)C1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2ccsc2C(NC(=O)c2ccccc2)C1O

Procedure:
The title compound was prepared as described in Example 34 starting with benzoyl chloride (0.95 ml), triethylamine (3.3 ml, 23 mmol) and 7-amino-5,6-dihydro-6-hydroxY-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.55 g, 7.78 mmol) in dichloromethane (35 ml) to give the product 1.07 g (45%) as a colorless solid; mp 219°-220° C.; IR(KBr):3398, 1657, 1526 and 1490 cm-1 ; MS:m/z 304 (MH+); 1H NMR (DMSO-d6):δ 1.21 (5,3H), 1.39 (5,3H), 3.81 (m,1H, simplifies to d, J=8.8 Hz, with D2O), 5.00 (m,1H simplifies to d, 5=8.8 Hz, with D2O), 5.61(d,J=6.0 Hz, 1H, exchanges with D2O), 6.58(d,J=5.3 Hz,1H), 7.29(d,J=5.3 Hz,1H), 7.47(m,3H), 7.92 (dd,J=1.3 Hz, J=8.2 Hz,2H) and 8.79 (d,J=8.3 Hz, 1H, exchanges with D2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:27])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[C:28](OCC)(=O)C.CO>[Pd]>[Cl:27][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([CH:24]([CH3:25])[CH3:26])[CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: CCOC(C)=O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Step D (31 mg, 0.072 mmol) was dissolved in ethyl acetate/methanol (1 ml/1 ml) and placed in a hydrogenation bottle with 10% palladium on carbon (90 mg). The mixture was placed on Parr shaker for two hours under 50 p.s.i. of hydrogen, then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate/methanol. The combined filtrate was concentrated to give the title compound (26 mg) as a clear, viscous oil that was used in the next step without purification. MS (APCl−) Calc: 439.0, Found: 438.1 (M−1).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8]P(OCC)(OCC)=O)(=[O:5])[CH3:4].[Br:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.C(OCC)C>C1COCC1>[Br:17][C:18]1[N:23]=[C:22]([CH:24]=[CH:4][C:3]([O:6][CH2:7][CH3:8])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
In THF (10 ml) was suspended sodium hydride (60%, 440 mg, 11.0 mmol), and to the mixture was added at −30° C. a solution of diethylphosphonoethyl acetate (2.47 g, 11.0 mmol) in THF (10 ml). The mixture was stirred at the same temperature for 30 minutes, and to the mixture was added at −30° C. a solution of 6-bromo-2-pyridinecarbaldehyde (1.86 g, 10.0 mmol) in THF (10 ml). While warming the temperature of the mixture from −30° C. to −10° C., the mixture was stirred for 1.5 hours. To the mixture was added diethylether (40 ml), and the mixture was washed with water (20 ml, 5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane (10 ml), and the mixture was cooled to 0° C. The precipitated insoluble materials were filtered, which were washed with hexane cooled to 0° C., and dried under reduced pressure to give ethyl 6-bromo-2-pyridineacrylate (2.00 g, 7.81 mmol, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:28][CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[S:28][CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (655 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (569 mg, yield: 92%). This was recrystallized from ethanol-hexane. Melting point: 121–122° C.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].N1C=CN=C1.[OH:24][C@H:25]([CH2:46][OH:47])[C@H:26]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[Si:5]([O:47][CH2:46][C@@H:25]([OH:24])[C@H:26]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc([C@@H](NC(=O)OCc2ccccc2)[C@H](O)CO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](NC(=O)OCc2ccccc2)[C@H](O)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
TBDPSCl (3.5 g, 12.6 mmol, 1.1 equiv) and imidazole (1.95 g, 28.7 mmol, 2.5 equiv) were added to a solution of 2.21.1b (3.8 g, 11.4 mmol, 1.0 equiv) in DMF (11.5 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl solution, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 0 to 50%) to give product 5.4 g (83% yield). MS m/z (M+Na) 592