Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2[C:10]([O:14][C:15]3[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.Cl.[NH2:23][C@:24]([CH3:30])([CH2:28][CH3:29])[C:25](O)=[O:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C.CC#N.C(OCC)(=O)C.O>[NH2:23][C@:24]([CH3:30])([CH2:28][CH3:29])[C:25]([NH:21][C:18]1[CH:19]=[N:20][C:15]([O:14][C:10]2[C:5]3[C:6]([CH3:8])([CH3:9])[O:7][C:2]([CH3:1])=[N:3][C:4]=3[CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)=[O:26]
Reactant: CC1=Nc2cccc(Oc3ccc(N)cn3)c2C(C)(C)O1
Reactant: CC[C@@](C)(N)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)OC(C)=N3)nc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
To a suspension of 6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]pyridin-3-amine (Intermediate 204, 185 mg, 0.65 mmol) and (R)-2-amino-2-methyl-butanoic acid hydrochloride (100 mg, 0.67 mmol) in ethyl acetate/MeCN (2 mL, 1:3 v/v mixture), a 50% w/w solution in ethyl acetate of T3P (0.43 mL) was added drop wise at 0° C. The mixture was then heated at 60° C. for 3 hours and at 80° C. for 4.5 hours. The mixture was cooled to room temperature diluted with water (5 mL) and ethyl acetate (10 mL), Two phases were separated and the aqueous one was treated with a saturated solution of NaHCO3 (pH=8) and back-extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 20:80 as eluent affording the title compound (143 mg) as a yellow foam.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:18])([F:17])[C:7]1[CH:8]=[C:9]([OH:16])[C:10](=[CH:14][CH:15]=1)[C:11](O)=[O:12].[NH3:19].Cl>C1(C)C=CC=CC=1.CN(C)C=O>[OH:16][C:9]1[CH:8]=[C:7]([C:6]([F:18])([F:17])[F:5])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:19])=[O:12]
Reactant: N
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(C(F)(F)F)cc1O
Reaction time: 0.17 h

Procedure:
Thionyl chloride (2.7 mL) and N,N-dimethylformamide (0.1 mL) were added to a toluene (50.0 mL) solution of 4-trifluoromethylsalicylic acid (5.0 g), and the reaction mixture was refluxed for 30 minutes. The reaction mixture was left to cool. The reaction mixture was then added dropwise to aqueous ammonia (50.0 mL) under ice cooling, and the reaction mixture was stirred at the same temperature for 10 minutes. The pH of the reaction mixture was adjusted to 3 with concentrated hydrochloric acid, and the reaction mixture was then extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 50:50). The title compound (1.84 g) was obtained as pale beige crystals.
Reaction SMILES: [Br:1][C:2]1[C:22]([C:23]([O:25]CC)=[O:24])=[C:5]2[S:6][CH:7]=[C:8]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][O:18][CH3:19])=[CH:11][C:10]=3[O:20][CH3:21])[N:4]2[N:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:22]([C:23]([OH:25])=[O:24])=[C:5]2[S:6][CH:7]=[C:8]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][O:18][CH3:19])=[CH:11][C:10]=3[O:20][CH3:21])[N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(Br)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(OC)c(-c2csc3c(C(=O)O)c(Br)nn23)c(OC)c1
Yield: 94.2 %

Procedure:
To an ethanol (60.0 mL) solution of ethyl 6-bromo-3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]pyrazolo[5,1-b][1,3]thiazole-7-carboxylate (3.84 g, 8.45 mmol) was added a 5N aqueous solution of sodium hydroxide (5.07 mL, 25.3 mmol) and heated to reflux for two hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water (30 mL) was added to the residue, a 5N aqueous solution of hydrochloric acid was added while cooling on ice so that the solution became acidic, and the precipitated solid was subjected to suction filtration and dried to obtain the title compound (3.4 g, 7.96 mmol).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:6][C@H:5]([S:12][C:13](=[O:15])[CH3:14])[CH2:4]1.C(O[C@H:20]1[O:37][C@@H:36]([CH3:38])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]1[O:22][C:23](=[O:25])[CH3:24])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:28]([O:27][C@@H:26]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:36]([CH3:38])[O:37][C@H:20]([O:1][CH2:2][C@@H:3]2[CH2:4][C@@H:5]([S:12][C:13](=[O:15])[CH3:14])[CH2:6][N:7]2[S:8]([CH3:11])(=[O:10])=[O:9])[C@@H:21]1[O:22][C:23](=[O:25])[CH3:24])(=[O:30])[CH3:29]
Reactant: CC(=O)O[C@H]1O[C@@H](C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)S[C@@H]1C[C@@H](CO)N(S(C)(=O)=O)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@H](OC[C@@H]2C[C@@H](SC(C)=O)CN2S(C)(=O)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of thioacetic acid (3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester (0.070 g) and 1,2,3,4-tetra-O-acetyl-6-deoxy-beta-L-mannopyranose [G. Hodosi and P. Kovàc, Carbohydr. Res., 303, 239–243 (1997)] (0.138 g) in dichloromethane (10.0 ml) was treated with trimethylsilyl trifluoromethanesulphonate (0.075 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, poured into a sodium bicarbonate solution, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:1 as eluent to obtain acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl ester (0.105 g) as a syrup, MS: 543 (M+NH4+). Acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl ester (0.080 g) was reacted as described for the S-Acetyl deprotection (see below) to obtain (2S,3R,4R,5R,6S)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3,4,5-triol (0.035 g) as a colourless foam, MS: 358 (MH+).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([N+:15]([O-:17])=[O:16])[C:3]=1[NH:4]C(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([N+:15]([O-:17])=[O:16])[C:3]=1[NH2:4]
Reactant: CC(=O)Nc1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(F)c(N)c([N+](=O)[O-])c(F)c1F
Temperature: 0 °C
Yield: 118.7 %

Procedure:
To 2,4,5-trifluoro-3-methyl-6-nitro-N-acetyl-aniline (2.08 g) are added ethanol (30 ml) and 10% hydrochloric acid (30 ml) and the mixture is refluxed for 3 hours. After cooling, the reaction mixture is poured into ice-water, neutralized with potassium carbonate, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitroaniline (2.05 g), as brown crystals.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21].[I-].ClC1C=CC=C[N+]=1C.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38].C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([O:22][C:37]1[CH2:36][CH2:35][CH2:34][C:33](=[O:38])[CH:32]=1)=[O:21]
Reactant: O=C(O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Reactant: O=C1CCCCC1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(OC(=O)c2cnc(-c3cccnc3)n(-c3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1,6-dihydro-6-oxo-1-phenyl-2-(3-pyridinyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 7, Step C) (10.7 g, 36.3 mmol) in dichloromethane (150 mL) at ambient temperature was added 2-chloro-N-methyl pyridinium iodide (also known as the Mukaiyama reagent) (14.8 g, 57.9 mmol) followed by cyclohexanedione (6.5 g, 58 mmol) and triethylamine (9.2 g, 91 mmol). The reaction mixture was left stirring at ambient temperature overnight, then diluted with dichloromethane, washed with water, brine and dried over anhydrous Na2SO4. The residue obtained after removal of the solvent under vacuum was purified by tituration with n-chlorobutane/petroleum ether mixtures to obtain 9.8 g of the title compound as a light brown solid.
Reaction SMILES: [C:1](=[O:26])([O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)[CH2:15][CH2:14]1)OC1C=CC([N+]([O-])=O)=CC=1.[CH:27]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([N:31]2[CH2:36][CH2:35][N:34]([C:1]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=4)[CH2:17][CH2:18]3)=[O:26])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Reactant: C1CC(N2CCNCC2)C1
Solvent: ClCCl
Product: O=C(OC1CCN(c2ccc(=O)[nH]n2)CC1)N1CCN(C2CCC2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl carbonate (440 mg, 1.22 mmol) in DCM (20 mL) was added TEA (616 mg, 6.1 mmol) and 1-cyclobutylpiperazine (388 mg, 1.83 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The title compound was obtained as a white solid after silica gel chromatography (DCM/MeOH=50/1 to 5/1) (410 mg, 93%). [1H NMR (400 MHz, CDCl3) δ 11.20 (s, 1H), 7.20 (d, J=10 Hz, 1H), 6.87 (d, J=10 Hz, 1H), 4.87˜4.92 (m, 1H), 3.45˜3.50 (m, 6H), 3.16˜3.23 (m, 2H), 2.68˜2.76 (m, 1H), 2.29 (br, 4H), 1.72˜2.07 (m, 10H); LCMS: Rt=1.36 min, m/z 362.3 (M+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([N:21]([CH3:22])[CH3:19])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C(=O)N(C)C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
44 g 5-tert-butyl-2-methoxy-3-nitro-benzoic acid are dissolved in 400 ml of tetrahydrofuran, combined with 31 g carbonyldiimidazole and stirred for 2 hours at 50° C. The mixture is cooled to ambient temperature, combined with 173 ml of a 2 M solution of dimethylamine in tetrahydrofuran and stirred for a further 16 hours at 50° C. Then it is diluted with ethyl acetate and washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel with chloroform.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(OCCCc3ccccc3F)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(/C=C/c1ccc(OCCCc2ccccc2F)c(C(F)(F)F)c1)(CO)CO
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 101-1 (600 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (370 mg) as a white powder.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]([NH:19][C:20]2[CH:25]=C[CH:23]=[CH:22][CH:21]=2)=[O:18])[C:12](=[O:26])[CH2:11][N:10]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38]C1C=CC=CC=1.NC1C=NC=CC=1>>[CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]([NH:19][C:20]2[CH:25]=[N:38][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:12](=[O:26])[CH2:11][N:10]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[C:9]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Agent: Nc1cccnc1
Product: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1cccnc1

Procedure:
Instead of the starting material compound of Example 273, that is, aniline, 3-aminopyridine was used for the similar procedure as in Example 273 to obtain the title compound.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Reaction time: 2.5 h
Yield: 135.4 %

Procedure:
2.0 g (5.2 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1) were dissolved, under nitrogen atmosphere and magnetic stirring, in 20 ml of THF. 2.0 g (14.5 mmol) of K2CO3, 0.87 ml (7.8 mmol) of ethyl bromoacetate and a small amount of Ki were added and the reaction mixture was left at room temperature under magnetical stirring for 2.5 hours. The precipitate was filtered off and the solution was evaporated in-vacuo to dryness; the residue was dissolved in water and extracted with EtOAc; the organic phase was separated, dried over Na2SO4 and evaporated in-vacuo to dryness to obtain 3.3 g of a dense yellow oil. The oil was purified by flash chromatography on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 70:30 containing 0.5% of 28% NH4OH, and the purified product was triturated with i-Pr2O/i-PrOH to yield 2.1 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH2:14]([NH2:16])[CH3:15].O>CC#N>[Cl:13][C:4]1[CH:3]=[C:2]([NH:16][CH2:14][CH3:15])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCN
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: O
Solvent: CC#N
Product: CCNc1cc(Cl)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (4.4 g, 20 mmol) in CH3CN (50 mL) was added dropwise a solution of ethylamine in water (65%, 2.7 g, 39 mmol) at 0° C., then the resulting mixture was stirred at RT overnight. The reaction was concentrated and the residue was washed with water to give ethyl 6-chloro-4-(ethylamino)nicotinate (3.9 g, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1 H), 8.08 (s, 1 H), 6.53 (m, 1 H), 4.19 (q, J=7.2 Hz, 2H), 2.78 (q, J=7.2 Hz, 2 H), 1.28 (t, J=7.2 Hz, 3 H), 1.13 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 229.1[M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6]Br)[CH3:2].[I:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:18]=[CH:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[C:14](=[O:23])[C:13]=2[CH:24]=1>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:14]1([OH:23])[C:13]2[CH:24]=[C:9]([I:8])[CH:10]=[CH:11][C:12]=2[CH:18]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2)[CH3:2]
Reactant: O=c1c2ccccc2ccc2ccc(I)cc12
Reactant: CCOCCCBr
Solvent: C1CCOC1
Product: CCOCCCC1(O)c2ccccc2C=Cc2ccc(I)cc21

Procedure:
3-Ethoxypropyl bromide (7.5 g., 0.045 mole) is converted to the Grignard reagent using standard procedures (see above). To this solution (ca 60 ml.), stirred in an ice bath, is added dropwise a solution of 10 g. (0.030 mole) of 3-iodo-5H-dibenzo[a,d]cyclohepten-5-one in 30 ml. of dry THF. The mixture is stirred for 5 minutes and concentrated in vacuo. The residue is treated with saturated ammonium chloride solution and extracted three times with ether. The ether layer is washed once with water, dried over sodium sulfate, and evaporated in vacuo to an orange solid, m.p. 95°-105° (12.0 g., 95%).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[CH3:9][C:10]1[CH:15]=[C:14]([C:16](=[O:25])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:13]=[CH:12][N:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]([F:4])([F:3])[C:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=1)([OH:25])[CH:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C(=O)C(C)c2ccccc2)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccccc2)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
Trifluoromethyltrimethylsilane (2N in THF, 0.76 mL, 1.5 mmol) was added at 0° C. to a solution of 1-(2-methyl-pyridin-4-yl)-2-phenyl-propan-1-one (142 mg, 0.63 mmol) in THF (5 mL), followed by the addition of tetrabutylammonium fluoride trihydrate (40 mg, 0.13 mmol). After stirring overnight at r.t., an additional amount of trifluoromethyl-trimethylsilane (0.38 mL), followed by tetrabutylammonium fluoride trihydrate (20 mg) was added to drive the reaction towards completion. The solvent was evaporated, the residue was taken up in methanol, and the title compound (42 mg, 23%) was isolated by reversed-phase, preparative HPLC (Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]). 1H NMR (300 MHz, DMSO-D6) 8.25 (1H, d), 7.17 (1H, s), 7.11 (2H, d), 7.09-7.00 (4H, m), 6.93 (1H, s), 3.62 (1H, q), 2.35 (3H, s), 1.42 (3H, d); MS (m/e)=296.4 [MH+].
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C@H:13]([OH:21])[C@H:14]([NH2:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1.CN(C1C=CC=CN=1)C.[CH2:31]([O:38][C:39](ON1C(=O)CCC1=O)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C@@H:6]2[C@@H:5]([C@H:13]([OH:21])[C@@H:14]([NH:20][C:39]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](N)[C@@H](O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](NC(=O)OCc1ccccc1)[C@@H](O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
A solution of ethyl (2R,3R)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-amino-3-hydroxypropanoate (3.05 g, 9.99 mmole, obtained from Reference Example 38), dimethylaminopyridine (250 mg, 2.1 mmole) and N-(benzyloxy)carbonyloxy succinimid (2.49 g, 10 mmole) in anhydrous methylene chloride (40 ml) was cooled at 0° C. under argon. Triethylamine (1.394 ml, 10 mmole) was introduced to this solution. The resulting mixture was warmed to room temperature and stirred at room temperature for 15 hours under argon, and the mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride:ether:methanol=93:5:2), to give ethyl (2R,3R)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-{[(benzyloxy)carbonyl]amino}-3-hydroxypropanoate as a white solid (2.92 g, 66%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:42]=[CH:43][CH:44]=1)[C:15]([NH:17][C:18]1[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:25][C:19]=1[O:20][CH2:21][C:22](O)=[O:23])=[O:16].[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:42]=[CH:43][CH:44]=1)[C:15]([NH:17][C:18]1[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:26]=[CH:25][C:19]=1[O:20][CH2:21][C:22]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:23])=[O:16]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc3ccccc3s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A mixture of 2-[3-(2-benzothiazolylmethoxy)benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid (200 mg, 0.31 mmol), methanesulfonamide (31 mg), 4-dimethylaminopyridine (45 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (125 mg) and dichloromethane (10 ml) was stirred at room temperature for 3 days. The reaction solution was washed with 1 N hydrochloric acid, water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. By recrystallizing the resulting solid material from acetonitrile (2 ml), 2-[2-[3-(2-benzothiazolylmethoxy)benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy]-N-(methanesulfonyl)acetamide 0.5 hydrate (70 mg, 0.096 mmol, 31%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][C:8]=1[OH:9])[OH:4].[Bi]=O.[Bi:14]>O>[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][C:8]=1[OH:9])[OH:4].[Bi+3:14].[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][C:8]=1[OH:9])[OH:4].[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][C:8]=1[OH:9])[OH:4]
Reactant: [Bi]
Reactant: O=C(O)c1c(O)cccc1O
Agent: O=[Bi]
Solvent: O
Product: O=C([O-])c1c(O)cccc1O
Product: [Bi+3]
Temperature: 50 °C

Procedure:
A 3-liter thermostatic reactor fitted with a pneumatic stirrer, a bottom valve, temperature probes, a reflux condenser and a heating system is employed for this synthesis. 900 ml of distilled water and 15.4 g of γ-resorcylic acid, that is 0.1 mole of acid, are placed in the reactor. The heterogeneous mixture is heated to 50° C. with stirring and then 31 g of bismuth oxide, that is 0.1 gram-atom of bismuth, are added portionwise over approximately 15 minutes. The suspension thus obtained is heated to 80° C. After approximately 30 minutes approximately 1500 ml of distilled water are added to permit better stirring of the suspension and the suspension is then left stirred for approximately 5 hours at 80° C. The mixture is then filtered hot and the cake obtained is then washed with 500 ml of ethanol. The product is next vacuum-dried at 60° C. over calcium chloride. At the end of reaction 24 g of bismuth γ-resorcylate are recovered.