Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C@H]2[C@@H](O)[C@H]([O:9][C@@H:10]3[C@@H:15]([OH:16])[C@H:14]([O:17][C@H:18]4[C@@H:22]5[C@@H:23]([OH:59])[C@H:24]([O:26][C@@H:27]6[C@@H:32]([OH:33])[C@H:31]([O:34][C@H]7[C@@H]8[C@@H](O)[C@H](O[C@@H]9[C@@H](O)C(O)O[C@H](CO)[C@@H]9O)O[C@H]7CO8)[O:30][C@H:29]([CH2:56][OH:57])[C@@H:28]6[OH:58])[O:25][C@H:19]4[CH2:20][O:21]5)[O:13][C@H:12]([CH2:60][OH:61])[C@@H:11]3[OH:62])O[C@@H]1[C@H]2O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>P([O-])([O-])([O-])=O>[CH2:20]1[O:21][C@H:22]2[C@H:23]([OH:59])[C@H:24]([O:26][C@@H:27]3[C@@H:32]([OH:33])[C@H:31]([OH:34])[O:30][C@H:29]([CH2:56][OH:57])[C@@H:28]3[OH:58])[O:25][C@@H:19]1[C@H:18]2[O:17][C@@H:14]1[O:13][C@H:12]([CH2:60][OH:61])[C@H:11]([OH:62])[C@H:10]([OH:9])[C@H:15]1[OH:16]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H]3OC[C@@H]2O[C@@H](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@H]4[C@H]5OC[C@@H]4O[C@@H](O[C@H]4[C@@H](O)[C@@H](CO)OC(O)[C@@H]4O)[C@@H]5O)[C@@H]2O)[C@@H]3O)[C@H](O)[C@@H](O[C@@H]2O[C@H]3CO[C@@H]([C@H]2O)[C@@H]3O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H]3OC[C@@H]2O[C@@H](O[C@@H]2[C@@H](O)[C@H](O)O[C@H](CO)[C@@H]2O)[C@H]3O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 3 h

Procedure:
An amount of 30 mg of neoagarohexaose was dissolved in 10 ml of phosphate buffer of pH 7.8. Into this solution, a solution of 0.1 ml of potassium phosphate buffer (pH 7.8) which dissolved 0.1 U of agarase 0107 isolated and purified from Vibrio sp. JT0107-L4 was added. The resultant solution was incubated at 30° C. for 3 hours, then a solution of 0.1 ml of phosphate buffer (pH 7.8) which dissolved 1.5 U of α-NAOS hydrolase isolated and purified from Vibrio sp. JT0107-L4 was added therein. The resultant solution was incubated at 30° C. for 5 hours. The reaction solution was applied to an activated carbon column (5 mmφ×50 mm), which was then washed with 1 ml of water and 1 ml of 10% ethanol followed by elution with 3 ml of 24% ethanol. The solvents of the 24% ethanol fraction were removed by distillation using a rotary evaporator. Thereafter, freeze-drying was applied and the weight was determined; the weight was 11.4 mg. This reaction product was analyzed by thin layer chromatography; thereby, a substance of Rf=0.3 (developing solvent; butanol:ethanol:water=3:1:1) was confirmed. In addition, the mass number of the reaction product was determined using a fast atom bombardment mass spectrometer and found to be 486. From these facts, the substance was identified as agarotriose. The yield of the resulting agarotriose was calculated as 76%. The structure of agarotriose is shown below. ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]2[C:6]1=[O:21].[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[NH2:26][C:23]1[CH:24]=[CH:25][C:2]([Cl:1])=[C:3]([CH:22]=1)[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]2[C:6]1=[O:21]
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cc(N)ccc1Cl
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a solution of Example 90 (20 mg, 0.05 mmol) in acetone (0.4 mL) and water (0.1 ml) was added zinc dust (33 mg, 0.5 mmol) followed by ammonium chloride (27 mg, 0.5 mmol) and the reaction mixture was stirred for 10 minutes. The reaction mixture was filtered through a pad of celite, extracted with DCM and the organic layers were collected. The organic layers were washed with brine, dried with Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to provide the desired compound (5 mg, 27%). MS (ESI): mass calcd. for C17H16ClN7O, 369.8; m/z found, 370.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.48 (d, J=1.2 Hz, 1H), 8.87-8.79 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.74 (s, 1H), 6.59 (d, J=8.4 Hz, 1H), 5.06 (d, J=16.3 Hz, 1H), 4.96 (d, J=11.9 Hz, 1H), 4.81-4.68 (m, 1H), 4.34 (d, J=16.1 Hz, 1H), 4.06 (s, 1H), 1.17 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a suspension of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (26.7 g; 100 mmol) (example 1I]) in dichloromethane (100 ml) was added at 0° C. 10.9 ml (150 mmol) of thionyl chloride within 0.5 hours. Stirring was continued at ambient temperature for 1 hour. Afterwards, ice water was added and the mixture was stirred vigorously. Then, the layers were separated, the aqueous phase was extracted with 100 ml of dichloromethane. The combined organic phases were washed with water, aqueous sodium hydrogen carbonate, brine, and dried over anhydrous sodium sulfate. After evaporation, 27.9 g of the title compound was obtained as light brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][OH:8].[ClH:9]>C1(C)C=CC=CC=1>[ClH:9].[CH3:7][O:8][C:5](=[NH:6])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: CO
Reactant: COCCC#N
Agent: Cl
Solvent: Cc1ccccc1
Product: COCCC(=N)OC
Temperature: 3 °C
Reaction time: 2.25 h
Yield: 80 %

Procedure:
To a 3-necked reaction vessel equipped with stirrer, gas delivery tube, thermometer and reflux condenser is charged 85.1 parts of 3-methoxypropionitrile, 32.0 parts of reagent grade methanol and 300 parts of toluene. The exit from the reflux condenser is connected to a drying tower filled with a commercially available drying agent and a bath is provided for cooling the vessel below 0° C. Hydrochloric acid gas flow is controlled by means of a rotameter and is passed through a calcium chloride filled trap which serves both as a means for drying the gas and as a receiver in case liquid is sucked back into the line. After charging the reagents and toluene, the solution is stirred and cooled to 3° C. and the HCl gas is then fed, while controlling the temperature to -4° to 1° C., until 38.0 parts have been added. The HCl gas is added as rapidly as possible commensurate with complete adsorption and good temperature control. The mixture is then stirred for 15 hours in an ice bath (maximum 10° C.). Crystals of methyl-3-methoxypropionimidate hydrochloride appear 2.25 hours after the HCl addition is complete. 46.5 Hours after the HCl addition is stopped, an 80% yield of methyl-3-methoxypropionimidate hydrochloride is formed.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[O:15][C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][CH2:7]1.C(N(CC)CC)C>CCOCC>[CH2:6]1[O:15][C:9]2([CH2:14][CH2:13][N:12]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
Methanesulphonyl chloride (24.8 g, 0.217mol) was added dropwise to a solution of 4-piperidone ethylene ketal (28.2 g, 0.197 mol) and triethylamine (30.2 ml, 0.217 mol) in ether (280 ml), and the reaction stirred at room temperature for 3 hours. The mixture was washed consecutively with water (2×), hydrochloric acid (1N), and saturated sodium bicarbonate solution, dried (MgSO4), filtered and evaporated in vacuo. The residue was triturated with hexane, filtered and dried to give the desired product as an off-white solid (41.6 g, 95%).
Reaction SMILES: [C:1](=[O:12])([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])N.[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1](=[O:12])([O:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCCCCOC(N)=O
Reactant: CC(C)CCCCCO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)CCCCCOC(=O)OCCCCCC(C)C
Temperature: 270 °C
Yield: 92.33 %

Procedure:
30.94 g of isooctyl carbamate, 48.90 g of isooctanol, 0.40 g of triphenylphosphine and 2.0 ml of a 20% strength solution of diisobutyl-aluminium hydride in toluene were warmed together, whilst stirring. The mixture started to boil at about 165° C. The mixture was now heated in such a way that a continuous reflux of isooctanol was set up in a Vigreux column (jacket length 30 cm) fitted on the reaction vessel. The temperature was raised continuously to 270° C. over a period of 7 hours; after that time 2.78 g (91.3% of theory) of NH3 had been separated off and 24.95 g of liquid and a little solid had been distilled off (isooctanol, urethane and urea). The mixture was then subjected to fractional distillation. A fraction of 4.35 g with a boiling point14 of 81.5 (isooctanol) and a fraction of 46.96 g with a boiling point~ 0.05 of 98-102 (diisooctyl carbonate) resulted. Yield 92.33%, based on urethane employed.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7](O)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:29])CC)C.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]([F:29])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2-(4-Chlorobenzyl)1,3-bis(1,2,4-triazol-1-yl)2-propanol (0.318g) was added to a solution of diethylamino sulphur trifluoride (0.128g) in chloroform (15ml), and the resulting yellow solution was stirred at room temperature for 3.5 hr. The mixture was then poured into water and the organic layer was separated, washed with water, dried, and evaporated to dryness. The yellow oil so obtained was purified by chromatography on a 25cm silica (Merck "Lobar") column, eluting with 3% v/v methanol in chloroform, to give a colourless oil which was crystallised from diethyl ether to give 2-(4-chlorobenzyl)-2-fluoro-1,3-bis(1,2,4-triazol-1-yl) propane, m.p. 161-163°.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[CH3:17][N:18]1[C:23]([N:24]2CCCN(C3C=CC=CC=3[N+]([O-])=O)[CH2:26][CH2:25]2)=[CH:22][C:21](=[O:40])[N:20]([CH3:41])[C:19]1=[O:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:17][N:18]1[C:23]([NH:24][CH2:25][CH2:26][N:4]([CH2:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:2]([CH3:1])[CH3:3])=[CH:22][C:21](=[O:40])[N:20]([CH3:41])[C:19]1=[O:42]
Reactant: Cn1c(N2CCCN(c3ccccc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O
Reactant: CC(C)NCCCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)N(CCCc1ccc([N+](=O)[O-])cc1)CCNc1cc(=O)n(C)c(=O)n1C
Yield: 178.1 %

Procedure:
N-(1-methylethyl)-3-(4-nitrophenyl)propylamine (0.6 g), 0.5 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6) and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in 30 ml acetonitrile, and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80° C. for 3 hours and subjected to silica gel column chromatograph (chloroform/methanol=40:1 (v/v)) for purification. Thus, 1.0 g of 1,3-dimethyl-6-{2-[N-(1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Reaction SMILES: C(NC(=O)/C=C(\O[C:11](=[O:30])[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=1[NH:23][CH2:24][C:25]1[O:29][CH:28]=[CH:27][CH:26]=1)/C)(C)(C)C.[CH3:32][N:33]([NH2:35])[CH3:34]>C(#N)C>[CH3:32][N:33]([CH3:34])[NH:35][C:11](=[O:30])[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[C:15]([Cl:22])=[CH:14][C:13]=1[NH:23][CH2:24][C:25]1[O:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)N
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Solvent: CC#N
Product: CN(C)NC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Reaction time: 24 h

Procedure:
N-tert-butyl-3-(2-furfurylamino-4-chloro-5-methylsulfonylbenzoyloxy)crotonamide (4.69 g.; 0.01 mole) and unsymmetrical-dimethylhydrazine (1.20 g.; 0.02 mole) are added to acetonitrile. The reaction mixture is refluxed with stirring for 24 hours. Additional unsymmetrical-dimethylhyrazine (1.20 g.; 0.02 mole) is added, and refluxing is continued for an additional 24 hours. The acetonitrile is removed under reduced pressure, and the dark residue is triturated with isopropyl alcohol. The tan colored solid which crystallizes is collected and dried, yield 2.4 g. (64%), m.p. 90° -104° C. Several recrystallizations from butyl chloride followed by a recrystallization from benzene yields 2-furfurylamino-4-chloro-5-methylsulfonylbenzoic acid 2,2-dimethylhydrazide in the form of a white solid, m.p. 169.5°-171° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[H-].[Na+].CI.[C:25](OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:25])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C

Procedure:
2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol 68 (175 mg) was cooled in DMF to 0° C. and then NaH was added at once. The reaction was allowed to warm to room temperature and stirred several minutes before addition of methyl iodide. Reaction was stirred several hours and monitored by LC-MS until complete. Ethyl acetate was added and the solution was extracted with saturated bicarbonate solution. Organic was collected and dried, filtered and concentrated to get crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH3:15]>>[Cl:1][C:2]1[C:3]([C:4]([NH:13][C@H:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])=[O:6])=[CH:7][C:8]([Cl:11])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 2,5-dichloronicotinic acid and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.42 (1H, d, J=2.6 Hz), 8.10 (1H, d, J=2.6 Hz), 8.04 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz), 6.82 (1H, d, J=7.3 Hz), 5.40–5.30 (1H, m), 3.92 (3H, s), 1.64 (3H, d, J=7.0 Hz); MS (ESI) m/z 353 (M+H)+, 351 (M−H)−.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:18][OH:19])=[C:6]([C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:20][C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].O>C1COCC1>[CH3:17][O:16][N:15]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[CH2:18][O:19][C:22]1[C:21]([Cl:20])=[CH:29][C:25]([C:26]([O:28][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:27])=[CH:24][N:23]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CNC(=O)C(=NOC)c1cccc(F)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1cccc(F)c1COc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.15 g, 3.7 mmol) was added to a solution of 3-fluoro-2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.54 g, 2.25 mmol) in dry THF (10 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. 5,6-Dichloronicotinic acid; t-butyl ester (0.59 g, 2.5 mmol) in 2-3 mL THF was added to this reaction mixture and stirred at 25° C. for about 2 hours. Water (40 mL) was added and the resulting mixture was extracted with ether (2×), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield 1.2 g crude oil. Oil was chromatographed with dry pack silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 pet ether/ethyl acetate as mobile phase. Elution and concentrated gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-3-fluoro-benzeneacetamide (520 mg) as an oil. (98% E isomer; 2% Z isomer).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][S:6]([C:9]1[C:10]([O:18][CH3:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])=[O:7]>CN(C)C=O>[Cl:5][S:6]([C:9]1[C:10]([O:18][CH3:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:3])=[O:13])(=[O:8])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(=O)O)cccc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1c(C(=O)Cl)cccc1S(=O)(=O)Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Three drops of N,N-dimethylformamide were added to a thionyl chloride (4.37 mL) suspension of 3-(chlorosulfonyl)-2-methoxybenzoic acid (3.00 g), followed by stirring at 60° C. for 2 hours. The solvent was evaporated, and this was azeotroped with toluene to obtain 3-(chlorosulfonyl)-2-methoxybenzoyl chloride (3.22 g).
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][N:21]4[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]4[CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[N:39]1([C:27]([C:25]2[N:26]=[C:20]3[CH2:19][N:18]([C:7]4[N:8]=[C:9]([NH:11][CH:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)[C:10]5[S:2](=[O:1])[CH2:3][CH2:4][C:5]=5[N:6]=4)[CH2:23][CH2:22][N:21]3[CH:24]=2)=[O:28])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: O=C(O)c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2)N1CCOCC1
Temperature: 25 °C

Procedure:
50 mg of 7-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (see 13.1) are placed in 2 ml dimethylformamide, then 66 μl diisopropylethylamine and 54.2 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min a suspension of 11.4 mg morpholine in 300 μl dimethylformamide is added. The reaction mixture is stirred at ambient temperature until there is no further reaction, and the product is purified directly by preparative HPLC (method B). 40 mg of Example 48 are obtained as a solid. Analytical HPLC-MS (method D): RT=0.79 min.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>CN(C=O)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:18])=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13][CH2:25][CH2:26][CH2:27][CH3:28])=[O:12])=[O:3]
Reactant: CCCCBr
Reactant: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Temperature: 50 °C
Yield: 57 %

Procedure:
4-[3-(Aminocarbonyl)-2,4-difluorophenoxy]-2-butenoic acid, mixture of isomeres (3:2) E:Z, (526 mg, 2 mmol, 1 equiv.) was dissolved in dry DMF (5 ml). K2CO3 (850 mg, 6 mmol, 3 equiv.) and n-butylbromide (0.23 ml, 2.1 mmol, 1.05 equiv.) were added and the reaction mixture was heated for 70 h at 50° C. and for 1.5 h at r.t. After cooling at r.t., the mixture was diluted with H2O (50 ml) and extracted with EtOAc (3×40 ml). The combined organic extracts were washed with H2O (6×30 ml), dried (MgSO4) and evaporated to dryness under reduced pressure. The oily residue was purified by column chromatography on silica, eluted with CH2Cl2 and MeOH/CH2Cl2 (1%), to give 364 mg, 57% yield, mp<40° C. HPLC-MS (method 1): m/z 314 [M+H]+, Rt=3.88 min. By 1H-NMR analysis it was determined to be a mixture of isomeres in a ratio (5:7) E:Z. When the same reaction was performed on the acid (3:40) E:Z mixture of isomeres, the product obtained was determined to be a mixture of isomeres in a ratio (1:4) E:Z.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:4]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#C[Si](C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)cn1
Reaction time: 0.67 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl 6-(2-(trimethylsilyl)ethynyl)pyridin-3-ylcarbamate (62 mg, 0.21 mmol) in THF (5 mL) was cooled to −15° C. and treated with 1.0 M tetrabutylammonium fluoride (Aldrich, 0.25 mL, 0.25 mmol) and stirred for 40 min. The mixture was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (45 mg, 100%) as an off-white solid. 1H NMR (DMSO-d6) δ 9.78 (s, 1H), 8.58 (d, 1H, J=2.5 Hz), 7.92-7.84 (m, 1H), 7.46 (d, 1H, J=8.6 Hz), 4.17 (s, 1H), 1.47 (s, 9H); MS(ESI+): m/z 219.20 (M+H)+.
Reaction SMILES: N1CCCC1.C(OC([O:13][C:14]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:40]=3[CH3:50])=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)(C)(C)C>O1CCCC1>[OH:13][C:14]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:40]=3[CH3:50])=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c1C
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Pyrrolidine (3 μl, 0.036 mmol) was added to a solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({3′-[(methoxycarbonyl)methyl]-2′-methyl-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (19 mg, 0.030 mmol) obtained in Example (33-4) in tetrahydrofuran (1 ml), and the mixture was stirred at 40° C. for 1 hour. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to give tert-butyl 2-hydroxy-6-[({3′-[(methoxycarbonyl)methyl]-2′-methyl-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate as a colorless oil (16 mg, yield: 100%).