Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1(C)[CH:8]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:7]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:6]2[S:5]1.[N-:31]=[N+:32]=[N-:33].[Na+].CC(C)=O>O>[N:31]([C:3]1([CH3:2])[CH:8]([C:9]([O:11][CH2:12][C:13]([Cl:15])([Cl:14])[Cl:16])=[O:10])[N:7]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:6]2[S:5][CH2:4]1)=[N+:32]=[N-:33]
Reactant: CC1(CCBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(N=[N+]=[N-])CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2,2,-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140° C.
Reaction SMILES: O1CCCC1.C1(C)C=CC(S(O[CH2:16][CH:17]2[S:29][C:21]3=[N:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:20]3[CH2:19][CH2:18]2)(=O)=O)=CC=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].[H-].[Na+]>O>[CH2:31]([N:33]([CH2:16][CH:17]1[S:29][C:21]2=[N:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:20]2[CH2:19][CH2:18]1)[CH2:34][CH3:35])[CH3:32]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CC1CCn2c(nc3ccccc32)S1
Yield: 40 %

Procedure:
Into 20 ml of tetrahydrofuran was dissolved 1.12 g (3 m mole) of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, followed by the addition of 5 ml of diethylamine. Then, a catalytic amount of sodium hydride was added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature andthen refluxed for eight hours. The reaction mixture was cooled and then condensed under reduced pressure. The reaction product was added with water and then extracted with chloroform. The chloroform layer was then dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and elutedwith chloroform to obtain 0.33 g (yield: 40%) of the intended product, m.p.93°-94° C.; IR νmaxKBr cm-1 : 3100-2800, 1420; Anal. Calcd. for C15H21N3S: C, 65.42; H, 7.68; N, 15.26; S, 11.64; Found: C, 65.33; H, 7.77; N, 15.49; S, 11.41.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:4][CH:3]=1.C[C@H:41]1[CH2:46][NH:45][CH2:44][CH2:43][N:42]1C(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:41]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:21]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(-c4cccc(C=O)c4)c3)c2)CC1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(-c2cccc(CN3CCNCC3)c2)c1)c1cccc(CC2CCNCC2)c1
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A solution of 1,1-dimethylethyl 4-{[3-({[(6-fluoro-3′-formyl-3-biphenylyl)methyl]amino}carbonyl)phenyl]methyl}-1-piperidinecarboxylate (74 mg, 0.14 mmol) in CH2Cl2 (5 mL) was mixed with 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (26 mg, 0.14 mmol) and NaB(OAc)3H (45 mg, 0.21 mmol). The resulting mixture was stirred for 16 hours, diluted with dichloromethane (30 mL) and washed with brine (10 mL). The organic layer was collected, dried over Na2SO4 and concentrated under vacuum. The residue was purified by loading onto a 2 g amminopropyl SPE cartridge, eluting sequentially with DCM (3×5 mL), EtOAc (3×5 mL), and MeOH (3×5 mL). The DCM fractions were combined, and mixed with 2 mL of TFA. After stirring for 1 h, the mixture was concentrated under vacuum, and the residue thus obtained was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (19 mg, 27%). LC/MS: m/z, 501 (M+H), 1.35 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([CH3:35])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.B(F)(F)F.[CH3:40][CH2:41][O:42]CC>C(O)CO>[C:30]([C:29]1([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[C:8]4[O:7][C:6]([C:4]([OH:3])=[O:5])=[CH:10][C:9]=4[CH:11]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:22][C:23]=2[CH3:35])[O:34][CH2:40][CH2:41][O:42]1)([CH3:31])([CH3:33])[CH3:32]
Reactant: CCOCC
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc(C)c2o1
Agent: FB(F)F
Solvent: OCCO
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid ethyl ester (506 mg, 1.06 mmol) in ethylene glycol (5.0 mL) is treated with BF3-Et2O (3.0 ml). The reaction mixture is heated to 80° C. and stirred for 3 h. The reaction is quenched with water (20 mL) and extracted with CH2Cl2 (30×2 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (8% EtOAc/Hex) to afford the title compound (550 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:65]([O:69][C:70]([NH:72][C:73]1[S:77][C:76]([C:78]2[C:83]([F:84])=[CH:82][CH:81]=[CH:80][C:79]=2[F:85])=[N:75][C:74]=1[C:86](O)=[O:87])=[O:71])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[F:85][C:79]1[CH:80]=[CH:81][CH:82]=[C:83]([F:84])[C:78]=1[C:76]1[S:77][C:73]([NH:72][C:70](=[O:71])[O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[C:74]([C:86](=[O:87])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:11]([OH:14])[CH2:12][CH2:13]2)[N:75]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
To a solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyazepan-4-yl)-2,2,2-trifluoroacetamide (504 mg, 1.57 mmol) in DCM (20 mL) was added DIPEA (1.65 mL, 9.42 mmol), PyBOP (1.17 mg, 2.20 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (559 mg, 1.57 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (240 mg, 23%). This solid (240 mg, 0.36 mmol) was stirred with HCl in 1,4-dioxane (4 M, 6 mL, 24 mmol) in MeOH (5 mL) at room temperature for 18 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 333. LCMS (ES+) m/z 464 (M+1)
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=O.CN1C=C([N+:15]([O-:17])=[O:16])C=C([N+]([O-])=O)C1=O.N>>[N+:15]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O-:17])=[O:16]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=c1cccc[nH]1
Agent: N
Product: O=[N+]([O-])c1ccccn1

Procedure:
In addition, compounds referred to hereinbelow as 7e and 7f were synthesized by modifying the method described by Tohda et al, Nucleophilic Reaction upon Electron-Deficient Pyridone Derivatives X. One-Pot Synthesis of 3-Nitropyridines by Ring Transformation of 1-Methyl-3,5-dinitro-2-pyridone with Ketones or Aldehydes in the Presence of Ammonia, Bull. Chem. Soc. Jpn. 1990, 63, 2820-2827, for producing nitropyridine by using 3,5 dinitro-1-methyl-2-pyridone which produced the nitro compound 7e which was reduced to the amine 7f.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:44]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccc(Cl)cc1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-(4-chloro-benzyl)-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CN(Cc1ccccc1)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.255 g, 0.97 mmol) and N-methyl-benzylamine (0.25 mL, 1.9 mmol) gives the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>[OH-].[Na+]>[CH2:18]([O:17][C:15]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:16])[CH:19]=[CH2:20]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 0 °C
Yield: 88 %

Procedure:
To a stirred solution of tyrosine (10 g) in 4N aq. sodium hydroxide (30 mL) cooled in an ice bath was slowly added allyl chloroformate (6.4 mL) in a period of 20 minutes. Ten minutes after completion of the addition the ice bath was removed and 4N aq. sodium hydroxide (30 mL) and H2O (5mL) were added. After two hours at RT MeOH (60 mL) was added. After an additional two hours the reaction mixture was extracted with Et2O. The aq. mixture was cooled in an ice bath, acidified to pH 2-3 using 36-38% hydrochloric acid and extracted with EtOAc. De organic extract was dried (Na2SO4) and concentrated under reduced pressure to give Alloc-Tyr-OH (38) as an oil (14.5 g, 88%). Rf 0.35 (DCM/MeOH/AcOH, 89/10/1, v/v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[H][H]>CO.C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: C=C(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F

Procedure:
760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(F)cc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.6 mg, 0.078 mmol) (from Example 3 supra) in THF (2 mL) were added diisopropylethyl-amine (22 mg, 0.170 mmol) (Aldrich) and then 4-fluorobenzoyl chloride (13.4 mg, 0.085 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 70/30) to give 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 29 mg, 82.5%).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[C:27]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:36]([CH2:35][CH2:34][CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]2=[O:8])[CH3:21]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 16, 3.5 g, 11.2 mmol), in N,N-dimethylformamide (33 ml) was added sodium hydrogen carbonate (3.3 g, 39 mmol) and 3-phenylpropylamine (10.6 g, 11.2 ml, 79.2 mmol). The mixture was heated to 150° C. for 12 h, then cooled to room temperature and partitioned between water (500 ml) and diethyl ether (500 ml). The organic layer was washed successively with water (4×250 ml). The aqueous layers were combined and extracted with diethyl ether (250 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (1.8 g, 43%).
Reaction SMILES: C(O[K])(C)(C)C.[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][OH:31])[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.CN(C=O)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:31][CH2:30][C:28]1[CH:29]=[C:22]2[C:21]([C:19](=[O:20])[NH:18][CH2:17][C:7]34[CH2:8][CH:9]5[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]5)[CH2:14]3)[CH2:16]4)=[CH:26][CH:25]=[CH:24][N:23]2[N:27]=1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccn2nc(CO)cc12
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 0.08 h

Procedure:
A 1.0 M solution of tBuOK in THF (0.3 mL) is added to a mixture of 2-hydroxymethyl-pyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)amide (73 mg, 210 μmol) and DMF (1 mL) at 0° C. under N2. After 5 min, ethyl bromoacetate (30 μL, 280 μmol) is added. The cold bath is removed and the mixture is left to stir for 23 h. 50% Sat. aq. NaHCO3 is added and the solution is extracted with EtOAc (20 mL). The organics are dried over Na2SO4, filtered and concentrated. Purification by PTLC (2:1 EtOAc:hexanes) affords the title compound as a pale yellow film. 1H NMR (400 MHz, CDCl3) δ: 8.50 (dd, 1H), 7.57 (d, 1H), 6.88 (s, 1H), 6.81 (dt, 1H), 6.27 (bs, 1H), 4.88 (s, 2H), 4.22 (q, 2H), 4.19 (s, 2H), 3.21 (d, 2H), 1.94-2.04 (m, 3H), 1.56-1.78 (m, 12H), 1.28 (t, 3H). LC-MS m/z (M+H+): 426.3; RT=1.31.
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:27](O)[CH3:28]>>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:20])[C:17]([O:19][CH2:27][CH3:28])=[O:18])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc2c(c1)Sc1ncccc1CC2
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)c1ccc2c(c1)Sc1ncccc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 40 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-9-yl)-propionic acid was added 15 ml of ethanol containing hydrogen chloride and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off to obtain the residue, to which was added ice-water, and the resulting mixture was alkalified with 5% sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain oily substance, which was chromatographed over silica gel, eluted with benzene/chloroform(1/1), and there was obtained 35 mg of ethyl 2-(5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-9-yl)-propionate as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[C:4]([OH:24])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCCl.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C@H:8]([OH:21])[CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:4]([O:24][C:35](=[O:37])[CH3:36])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H](O)COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)Oc1cc(Cl)ccc1OC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
To a reaction vessel were added (R)-1-(4-chloro-2-hydroxyphenoxy)-3-phthalimido-2-propanol 348 mg (1.00 mmol), sodium carbonate 159 mg (1.50 mmol) and 1,2-dichloroethane 4 mL. After to the mixture was dropped acetic anhydride 122 mg (1.20 mmol), the mixture was stirred at room temperature for 15 hours. After terminating the reaction by adding water, the water layer was removed and the organic layer was washed with an aqueous 5% HCl solution and an aqueous 5% NaCl solution successively. The organic layer was taken and the solvent was evaporated to give crude (R)-1-(4-chloro-2-acetoxyphenoxy)-3-phthalimido-2-propanol 372 mg (yield 92%, chemical purity 97%) as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([O:14][C:15](=[O:32])[CH2:16][CH2:17][NH:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:32])[CH2:16][CH2:17][N:18]([C:8](=[O:10])[CH3:9])[CH:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:13]
Reactant: CCOC(=O)CCNC1c2ccccc2-c2ccccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C(C)=O)C1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.51 mg of triethylamine and 0.28 ml of acetyl chloride were added under ice-cooling to a solution of 0.77 g of N-(9-fluorenyl)-β-alanine ethyl ester in 25 ml of methylene chloride. The resultant mixture was stirred at 0° C. for 0.5 hour and, then, at room temperature for 3 hours. The reaction solution was poured into ice-cold 1N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with saturated sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: chloroform-methanol) to give 0.85 g of N-acetyl-N-(9-fluorenyl)-β-alanin ethyl ester.