Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].N.[CH3:3][O:4][C:5](=[O:19])[C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:7][CH:8]=[O:9].C(Cl)(Cl)Cl.[CH2:24]1COC[CH2:25]1>>[CH3:3][O:4][C:5](=[O:19])[C@@H:6]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:25][CH2:24][CH2:18]2)=[CH:14][CH:15]=1)[CH2:7][CH:8]=[O:9]
Reactant: COC(=O)[C@H](CC=O)c1ccc(N(C)C)cc1
Reactant: C1CCOC1
Agent: N
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC=O)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-4-oxo-2-(4-pyrrolidin-1-yl-phenyl)-butyric acid methyl ester (2.23 g, 8.53 mmol, 1.00 equiv) in THF (15 mL) was added carefully to a stirring suspension of lithium aluminum hydride (1.27 g, 33.5 mmol, 4.0 equiv) in Et2O (45 mL). After 5 min, this mixture was diluted with saturated aqueous sodium potassium tartrate (100 mL) and Et2O (100 mL) and allowed to stir for an additional 8 h. The organic layer was separated and the aqueous was extracted three times with CH2Cl2. The combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (100% EtOAc) to afford 1.97 g (8.37 mmol, 98% yield) of a white solid assigned as S17; [α]D=−19.1 (c=1.03, CHCl3). This compound was then exposed to tert-butyldimethylsilyl chloride (2.83 g, 18.8 mmol, 2.20 equiv), triethylamine (2.63 mL, 18.8 mmol, 2.2 equiv), and CH2Cl2 (20 mL). After 7.5 h, the reaction mixture was subjected directly to silica gel chromatography. Gradient elution with 10–20% EtOAc in hexanes followed by concentration in vacuo afforded 3.41 g (7.37 mmol, 86% yield) of a faint-yellow oil. A portion of this substance (1.17 g, 2.53 mmol, 1.00 equiv) was dissolved in CH3I (0.47 mL, 7.6 mmol, 3.0 equiv) and stirred for 48 h and subsequently diluted with Et2O and filtered to provide 1.484 g of a yellow solid. A portion of the ammonium salt (128 mg, 0.200 mmol, 1.00 equiv) was suspended in THF (20 mL) and added to a stirring solution of dissolved sodium (18.4 mg, 0.800 mmol, 4.00 equiv) in freshly condensed liquid ammonia (25 ml) at −78° C. After 30 min, the reaction mixture was quenched with excess methanol, diluted with ether (20 mL) and allowed to warm to ambient temperature. The ethereal solution was washed with aqueous HCl (1N) and saturated NaCl and subsequently dried over Na2SO4. This residue was purified by silica gel chromatography to afford 52.0 mg of S11 (0.132 mmol, 61% yield) that was spectroscopically identical in all respects to the S11 generated above from (R)-4-oxo-2-(4- dimethylamino-phenyl)-butyric acid methyl ester. [α]D (reference)=−22.0 (c=1.08, CHCl3); [α]D (observed)=−22.8 (c=0.92, CHCl3).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1N=[CH:7][NH:6][CH:5]=1>N[C@H](C(O)=O)CCCNC(=N)N>[NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[C:5]2[C:7](=[CH:9][CH:2]=[CH:3][CH:4]=2)[NH:6][CH:5]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
10 ml 8% arginine (m/v), 0.4% histidine (m/v)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:24][C@H:23]([CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][C@H:12]1OC1N=CC(=S(=O)=O)N=1.[FH:46].F.F.C(N(CC)CC)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:24][C@H:23]([CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][C@@H:12]1[F:46]
Reactant: F
Reactant: O=S(=O)=C1C=NC(O[C@@H]2C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2n2cnc3c(Cl)ncnc32)=N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: F[C@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
113 mg (0.176 mmols) of 6-chloro-9-[2-O-(sulfurylimidazolyl)-3-deoxy-5-O-(triphenylmethyl)-β-D-erythro-pentofuranosyl]-9H-purine was dissolved in 1.80 ml of toluene, to which was added 0.18 ml (1.06 mmols) of triethylamine trihydrofluoride, and stirred overnight at 50° C. After having been cooled, 10.0 ml of ethyl acetate and 8.0 ml of an aqueous saturated solution of sodium hydrogencarbonate were added to this, to separate it into layers. The organic layer was dried with anhydrous sodium sulfate, and filtered. Then, the solvent was evaporated from the filtrate. The residue was dissolved in acetonitrile and analyzed through liquid chromatography. The intended product was obtained at an yield of 41.9%.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([O:58][C:59](=[O:79])[CH2:60][C:61]1([C:76](O)=[O:77])[CH:65]([CH3:66])[CH2:64][N:63]([CH2:67][C:68]2[C:73]([Cl:74])=[CH:72][CH:71]=[CH:70][C:69]=2[Cl:75])[CH2:62]1)([CH3:57])([CH3:56])[CH3:55]>O.CN(C)C=O>[Cl:75][C:69]1[CH:70]=[CH:71][CH:72]=[C:73]([Cl:74])[C:68]=1[CH2:67][N:63]1[CH2:64][C@@H:65]([CH3:66])[C@@:61]([CH2:60][C:59]([O:58][C:54]([CH3:55])([CH3:57])[CH3:56])=[O:79])([C:76](=[O:77])[NH:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12][CH2:11]2)[CH2:62]1
Reactant: CC1CN(Cc2c(Cl)cccc2Cl)CC1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCN1CCC(N)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3Cl)C[C@H]2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
1-Hexylpiperidin-4-amine obtained in Example 10a (894 mg, 4.85 mmol), triethylamine (1.04 ml, 7.46 mmol), N,N-dimethylformamide (10 ml) and PyBOP (2.52 g, 4.85 mmol) were added to (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 10g (1.5 g, 3.73 mmol), followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. This was concentrated, and the crude product was purified by column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give a white solid (1.85 g). This was optically resolved by HPLC (CHIRALPAK IA (3 cm diameter×25 cm), elution solvent: ethanol/hexane=6/94, flow rate: 20 ml/min.) to give a chiral form corresponding to the peak with a shorter retention time (875 mg).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][CH:11]=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](O)(=[O:28])[CH2:26][CH3:27].CCN=C=NCCCN(C)C>C(OCC)(=O)C.C1COCC1>[C:25]([O:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][CH:11]=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)O
Reactant: NS(=O)(=O)c1csc(C(=O)c2ccc(O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc(C(=O)c2cc(S(N)(=O)=O)cs2)cc1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
0.10 g (0.35 mmol) of 5-(4-hydroxybenzoyl)-3-thiophene sulfonamide, 85 mL (1.05 mmol) of pyridine, 26 mL (0.35 mmol) of propionic acid and 70 mg (0.37 mmol) of EDCI were added to 3.5 mL of THF. The reaction was stirred at rt for 46 h. The solution was diluted with ethyl acetate and washed with water (3×) followed with brine. The solution was dried over MgSO4 and the solvent removed under vacuum. Flash chromatography utilizing 1:1 ethyl acetate/hexane recovered 77 mg of 5-(4-propionoxybenzoyl)-3-thiophene sulfonamide as a clear colorless oil.
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].N1C2C(=CC=CC=2)C=CC=1.C(OC)(=O)CCCC=CCCCC.C(OC)(=O)CCCCC=CCCC.C(O)(=O)CCCCC=CCCC>>[C:7]([OH:9])(=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(Br)CCCCC(=O)OC
Agent: CCCC=CCCCCC(=O)O
Agent: CCCC=CCCCCC(=O)OC
Agent: CCCCC=CCCCC(=O)OC
Solvent: c1ccc2ncccc2c1
Product: CCCCC=CCCCC(=O)O
Yield: 35 %

Procedure:
Methyl 6-bromodecanoate (1.2 g) and quinoline (1.2g) were mixed together, and then allowed to react at 240° C. for 5 minutes. After the reaction was completed, the reaction solution was extracted with ether, washed with dilute sulfuric acid, washed with water, dried, evaporated to remove the solvent, and then distilled, thereby giving a mixture of methyl 5-decenoate and methyl 6-decenoate (310 mg). The mixture was hydrolyzed in a coventional manner, thereby giving a mixture (270 mg) of 5-decenoic acid and 6-decenoic acid (1/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH2:21][NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:20]=1)[CH2:5][N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CCN(CC)CC.[Cl:34][C:35]1[C:36]([OH:46])=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH2:21][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:42]([C:37]2[CH:38]=[C:39]([Cl:41])[CH:40]=[C:35]([Cl:34])[C:36]=2[OH:46])(=[O:43])=[O:44])[CH:20]=1)[CH2:5][N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)C(=O)OC(C)(C)C)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of tert-butyl 3-chloro-5-((isobutylamino)methyl)benzyl(isobutyl)carbamate (2.4 g, 6.27 mmol) in CH2Cl2 (30 mL) was added Et3N (1.3 mL, 9.40 mmol), followed by the addition of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (1.80 g, 6.89 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was diluted with CH2Cl2 and water. The organic layer was washed with saturated NaHCO3 solution, NH4Cl solution, brine solution, and dried over MgSO4. The filtrate was concentrated and the residue was purified by silica gel flash chromatography. The column was eluted with hexane to 80% dichloromethane in hexane. The fractions containing the desired product were combined and concentrated to give colorless viscous solid (2.8 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11](Br)[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[CH:7]=1)=[O:5])[CH3:2].[Cl-].[Li+].[CH2:20]([Sn](CC)(CC)CC)[CH3:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH3:21])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CCOC(=O)c1cc(C)nc2c(Br)cccc12
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nc2c(CC)cccc12
Temperature: 100 °C
Yield: 52 %

Procedure:
8-Bromo-2-methylquinoline4-carboxylic acid ethyl ester (0.5 g), lithium chloride (0.216 g), tetraethyltin (0.435 g) and bis(triphenylphosphine)palladium (II) chloride (0.05 g) were combined in dimethylformamide (20 ml) and heated at 100° C. for 24 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and filtered. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 5% diethyl ether/pentane) to give the title compound (0.215 g). m/z (API+): 244 (MH+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[N:18][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[OH:28].Cl>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[N:18][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[OH:28])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(=O)OCc3ccccc3)cc2c1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Benzyl chloroformate (7.5 g.) was added to a stirred solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (4.66 g.) in pyridine (75 ml.). The solution was stirred for 18 hours at room temperature and for 2 hours at 100° C. The solution was cooled and was poured onto a mixture of ice (500 g.) and 5N-hydrochloric acid (200 ml.). The pale solid which was precipitated was filtered off, washed with water, and recrystallised from a mixture of ethanol and water to give ethyl 6-benzyloxycarbonylamino-4-hydroxycinnolin-3-yl carboxylate, m.p. 250°-252° C.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[F:20][C:21]([F:30])([F:29])[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:20][C:21]([F:30])([F:29])[C:22]([NH:24][CH2:25][C:26]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:27])=[O:23]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Reactant: O=C(O)CNC(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)CNC(=O)C(F)(F)F)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
4′-C-Aminomethylthymidine (4) (0.14 mmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL). N-Trifluoroacetylglycine (0.036 g, 0.21 mmol) and O-(N-succimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TSTU] (0.085, 0.28 mmol) were then added and the solution stirred at ambient temperature. Diisopropylethylamine (0.036 g, 0.28 mmol, 0.05 mL) was then added dropwise to the solution with stirring. After 12 hours the solvent was removed under vacuum and the residue redissolved in dichloromethane:methanol (9:1). Applied solution directly to a silica gel column and eluted with dichloromethane:methanol (9:1). Fractions containing the desired material were pooled and the solvent removed under vacuum to give the title compound (5) as a clear, glassy material (0.28 g, 28% from crude 4). δH(300 MHz, CD3OD) 7.91(1H, s, H-6), 6.27(1H, dd, H-1′), 4.49(1H, dd, H-3′), 3.74(2H, s, glycyl CH2), 3.52(1H, d, H-5′), 3.51(2H, s, 4′-C—CH2), 3.43(1H, d, H-5′), 2.32(2H, m, H-2′), 1.68(3H, s, 5-CH3); ES +ve m/z 425(M+H)+, 442(M+H2O)+, 447(M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:33](=[O:34])[O:32][C:14]4=[N:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][CH:18]=[C:13]4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(-c4nc5c(Cl)cccc5s4)c(=O)oc3n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1oc2nc(N3CCNCC3)ccc2cc1-c1nc2c(Cl)cccc2s1
Reaction time: 16 h

Procedure:
To a suspension of t-butyl 4-(3-(4-chlorobenzo[d]thiazol-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (850 mg, 1.7 mmol) in CH2Cl2 (15 mL) was added 4N HCl in dioxane (5 mL). The mixture was stirred for 16 hours, and filtered. The solid was washed with ether and dried under nitrogen. 3-(4-Chlorobenzo[d]thiazol-2-yl)-7-(piperazin-1-yl)-2H-pyrano[2,3-b]pyridin-2-one hydrochloride was obtained quantitatively and used for the next step without further purification. MS m/z 399.1 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.12 (1H, s), 9.11 (2H, br), 8.36 (1H, d, J=8.8 Hz), 8.16, (1H, d, J=6.9 Hz), 7.66 (1H, d, J=8.8 Hz), 7.45 (1H, t, J=7.9 Hz), 7.14 (1H, d, J=8.8 Hz), 4.03 (4H, m), 3.26 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:40])([F:39])[C:24]1[CH:25]=[C:26]([NH:34][C:35](=[O:38])[CH2:36]Cl)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>CC#N>[F:22][C:23]([F:39])([F:40])[C:24]1[CH:25]=[C:26]([NH:34][C:35](=[O:38])[CH2:36][N:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=3[N:6]=[CH:7]2)[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Reactant: O=C(CCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c2c1C
Yield: 93.9 %

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (1.62 g, 7.2 mmol) in CH3CN (35 mL) was added K2CO3 (1.0 g, 7.24 mmol), KI (1.2 g, 7.23 mmol), and N-(3,5-bis(trifluoromethyl)phenyl)-2-chloroacetamide 1 (2.2 g, 7.19 mmol). The reaction mixture was refluxed overnight and quenched with H2O (100 mL). The resultant precipitate was filtered and dried to afford 3.33 g of methyl 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as a solid (yield: 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]#[N:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37]>C(O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13](/[C:15](=[N:36]/[OH:37])/[NH2:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:32])([F:33])[F:31])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(C#N)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(/C(N)=N/O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 80 °C

Procedure:
A mixture of the product of Step A of Example 2 (0.12 g, 0.25 mmol), hydroxylamine hydrochloride (43.48 mg, 0.626 mmol) and TEA (0.087 mL, 0.626 mmol) in ethanol (1.2 mL) in a sealed tube in Ar was heated at 80° C. overnight. After removal of solvent, the residue was partitioned between EtOAc and brine, separated, dried over Na2SO4. Purification by CombiFlash (eluent: 8% methanol in DCM) gave the product as a white solid. 1H-NMR (400 MHz, CDCl3): δ 1.30-1.45 (m, 9H), 1.70-1.99 (m, 3H), 2.38 (br. s., 1H), 3.09 (d, J=9.3 Hz, 3H), 3.28-3.54 (m, 3H), 3.65-3.89 (m, 3H), 4.23 (d, J=5.1 Hz, 1H), 4.44-4.93 (m, 5H), 7.72 (br. s., 1H), 8.69 (s, 1H); LC/MS: C23H31F3N6O4: m/z 513 (M+H).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: N#Cc1ccccc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Combine 2-iodobenzonitrile (9.0 g, 38.5 mmol), 4-bromophenylboronic acid (10.4 g, 51.8 mmol), 2M aqueous sodium carbonate (20 mL) and tetrakis(triphenylphosphine)-palladium(0) (4.5 g, 3.9 mmol) in 300 mL of dioxane and heat to 80° C. under nitrogen with stirring. After 3 hours cool to room temperature and dilute with 900 mL of ethyl acetate. Wash with water (2×50 mL), brine (1×50 mL) and dry over sodium sulfate. Filter and evaporate to a yellow solid. Chromatograph on silica gel two times, eluting with a gradient of 100% toluene to 1/9 ethyl acetate/toluene to give the title compound as a tan solid, 5.42 g (55%). MS (FAB)=257 (M+); HPLC analysis is 95%.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[N:28](CC4C=CC(OC)=CC=4)[N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:40][CH2:41][C:42]([F:44])([F:45])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c(Cl)cc2C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OCCCOc2cc(NC(=O)c3nnn[nH]3)c(C)cc2Cl)c(CCC(F)(F)F)c1O

Procedure:
A solution of 3 g (4.5 mmol) of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is refluxed for 60 minutes. The reaction mixture is concentrated under reduced pressure, about 150 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide thus obtained, of melting point 236°-238° (decomposition) is dissolved in 50 ml of tetrahydrofuran, and one equivalent of sodium, dissolved in 5 ml of methanol, is added. After addition of ether, crystallisation starts. The sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methylphenyl}}-1 H-tetrazole-5-carboxamide of melting point 90° (decomposition) is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:37])=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:29][CH:28]=3)[O:31][C:32]=2[CH3:37])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 120 f], 2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid as white solid.