Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:5][C@H:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[S:14]([O:1][C:2]1[C:3]([O:5][C@H:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4])([CH3:13])(=[O:16])=[O:15]
Reactant: COC(=O)C1=C(O)C(=O)O[C@@H]1C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=C(OS(C)(=O)=O)C(=O)O[C@@H]1C

Procedure:
137.76 g of (R)-2-hydroxy-3-methoxycarbonyl-2-penten-4-olide are dissolved in 660 ml of toluene and at -10° C. 110 g of methanesulphonyl chloride and then, within a period of 1 hour, 97 g of triethylamine, are added. 350 ml of water and 150 ml of saturated sodium chloride solution are added, the toluene product phase is removed and the aqueous phase is re-extracted twice with 250 ml of toluene. The toluene phases are washed with sodium chloride solution and with water and concentrated by evaporation. Orange-red oil, [α]D20 =+10.6° (3% in CHCl3).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.FCCN(CCF)C1C=CC(C#N)=C(C(F)(F)F)C=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>C(#N)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][CH2:2][F:1])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: N#Cc1ccc(NCCF)cc1C(F)(F)F
Reactant: COC(=O)CBr
Agent: N#Cc1ccc(N(CCF)CCF)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CN(CCF)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 50 %

Procedure:
To a solution of a 6:1 mixture of 4-[(2-fluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-[bis(2-fluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g) in acetonitrile (3 mL) was added Cs2CO3 (0.169 g, 0.52 mmol) and methyl bromoacetate (0.080 g, 0.52 mmol). The mixture was heated at 85° C. for 2 h. Upon cooling, additional methyl bromoacetate (0.080 g, 0.52 mmol) was added and heated at 85° C. for 8 h. Upon cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by radial chromatography (10-80% EtOAc-hexanes gradient) to give 0.052 g (50% yield) of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.9 Hz, 1H), 6.92 (d, J=2.7 Hz, 1H), 6.76 (dd, J=8.9, 2.7 Hz, 1H), 4.68 (dt, J=47.0, 4.8 Hz, 2H), 4.21 (s, 2H), 3.81 (dt, J=25.6, 4.8 Hz, 2H), 3.78 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[O:12])=[C:2]([F:1])[CH:7]=1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)COc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of 5-[3-(2-fluoro-4-hydroxy-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (71 mg) in N,N-dimethylacetamide (1.5 ml) were added ethylbromoacetate (36 mg) and cesium carbonate (69 mg). The mixture was stirred for 3.5 h at room temperature. Water was added and the mixture was extracted with diethyl ether. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give the title compound (77 mg) as a light brown oil, MS (ESI+): m/z=452.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19]OS(C)(=O)=O)[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][N:25]=[N+:26]=[N-:27])[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
0.450 g (1.27 mmole) (3RS)-1-(N-benzyloxycarbonylamidino)-3-mesyloxymethyl pyrrolidine and 0.124 g (1.9 mmole) of sodium azide were dissolved in 10 ml dimethylformamide and heated to 60° C. for four hours followed by stirring at room temperature over night. Water was added and the mixture was extracted twice with toluene/ethyl acetate 2/1. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2 /MeOH 95/5 as eluent to yield 0.262 g (68%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[Cl:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:13][C:14]1[C:19]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=2)=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1nccnc1Cl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2nccnc2Cl)cc1
Temperature: 70 °C

Procedure:
To a solution of 4-hydroxybenzoic acid ethyl ester (55.21 g, 332.3 mmol) and 2,3-dichloropyrazine (49.50 g, 332.3 mmol) in DMSO (300 mL) was added cesium carbonate (129.9 g, 398.7 mmol). The mixture was heated to 70° C. until the starting material was consumed. The mixture was cooled to RT, diluted with water and DCM, the layers were separated and the aqueous layer was extracted with DCM (2×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was washed with copious amounts of methanol and dried to give ethyl 4-(3-chloropyrazin-2-yloxy)benzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[S:24].[H-].[Na+].O>CN(C=O)C>[CH3:17][C:12]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:3]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: S=c1cccc[nH]1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
5-Bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (56.9 g, 196 mmol) and pyridine-2(1H)-thione (22.9 g, 206 mmol) were dissolved in DMF (400 mL) and cooled to 0° C. NaH (4.94 g, 206 mmol) was added portionwise and warmed to ambient temperature. The reaction was stirred for 18 hours and then poured into 2.5 L of water and stirred for 30 minutes The solids were filtered to provide 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (60.8 g, 190 mmol, 96.8% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:9][O:10][CH2:11]Cl.C(N(CC)C(C)C)(C)C.N.Cl.[CH2:24]([O:26][CH2:27]C)C>ClCCl>[CH3:9][O:10][CH2:11][O:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][O:1][CH2:24][O:26][CH3:27]
Reactant: CC(C)(CO)C(=O)O
Reactant: COCCl
Reactant: CCOCC
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC(C)(C)C(=O)OCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-hydroxy-2,2-dimethylpropionic acid [CAS No. 4835-90-9] (10 g) and dichloromethane (350 mL), at 0° C., chloromethyl methyl ether (16.1 mL) dissolved in dichloromethane (30 mL) and N,N-diisopropylethylamine (44.2 mL) were sequentially added. After stirring the mixture overnight at room temperature, aqueous ammonia (50 mL) was added thereto. To the mixture, 2 N hydrochloric acid (500 mL) and diethyl ether (800 mL) were added, and the resulting mixture was shaken, followed by collection of the organic layer. The organic layer was sequentially washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and saturated aqueous sodium chloride solution (300 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the obtained filtrate was concentrated under reduced pressure to obtain the captioned compound (16.5 g).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.CCN=C=NCCCN(C)C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CN(C=O)C.ClCCl>[Cl:21][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]([NH:36][CH2:35][CH2:33][OH:34])=[O:16])=[CH:12][C:11]=1[S:17](=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)NCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To furosemide (1.013 g, 3.0627 mmol) in DMF (3 mL) was added EDAC (608.3 mg, 3.173 mmol) in dichloromethane (3 mL) and then ethanolamine (185 μL, 3.065 mmol). The reaction solution was stirred at ambient temperature for 3 hours, and concentrated to dryness under high vacuum. The crude product was treated with water, and the resultant gum collected and chromatographed on silica gel eluting with methanol:dichloromethane (1:20) to give the title compound (476 mg, 42% yield). Mp 183-185° C. 1H NMR (300 MHz, CD3OD) δ8.17 (s, 1H), 7.45 (m, 1H), 6.94 (s, 1H), 6.37-6.36 (m, 1 H), 6.32-6.31 (m, 1H), 4.44 (s, 2H), 3.70-3.66 (m, 2H), 3.32-3.29 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 170.4, 153.0, 152.7, 143.6, 136.7, 131.3, 127.5, 114.8, 114.4, 111.4, 108.5, 61.5, 43.2, 40.7. LRMS (APIMS) m/z 374(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])[C:5]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[O:23])[C:5]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=1
Reactant: O=C(O)c1cccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNC(=O)c1cccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.3 %

Procedure:
3-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoic acid (0.080 g, 0.17 mmol) and N1,N1-dimethylethane-1,2-diamine (0.020 g, 0.23 mmol) were dissolved in DMF. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.037 g, 0.19 mmol) and HOBT-H2O (0.029 g, 0.19 mmol) were then added. N,N-Diisopropylethylamine (0.034 mL, 0.19 mmol) was added last. The reaction was stirred at ambient temperature for 2 days. The material was diluted with water and the solid was filtered and recrystallized in EtOAc/hexanes to afford the title compound (0.030 g, 33% yield) as a white solid. 1H NMR (CDCl3) δ 2.25 (s, 6H), 2.50 (t, 2H), 3.46-3.51 (m, 2H), 6.91 (bs, 1H), 7.28-7.37 (m, 3H), 7.62 (d, 1H), 7.68 (s, 1H), 7.86 (d, 1H), 7.97 (s, 1H), 8.41 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH2:8][C:7]2[O:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:27][C:26]=1[CH3:32]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1COc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of [4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.108 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.078 g, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.8 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 448 (M++H).
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.Cl.OC([C@@H]1CCCN1C(=O)[C@@H]1CCCN1)COC1C=CC(OC)=CC=1.C([O:48][C:49]([N:51]1[CH2:74][CH2:73][CH2:72][C@H:52]1[C:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[CH:60]([OH:71])[CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1)=[O:54])=O)(C)(C)C.Cl.O1CCOCC1>C(N(CC)CC)C>[OH:71][CH:60]([C@@H:56]1[CH2:57][CH2:58][CH2:59][N:55]1[C:53](=[O:54])[C@@H:52]1[CH2:72][CH2:73][CH2:74][N:51]1[C:49]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:48])[CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: COc1ccc(CN)cc1
Agent: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2)cc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(O)COc2ccc(OC)cc2)cc1

Procedure:
By the same procedure as in Example 24-A) using trichloromethyl chloroformate (0.20 ml), 4-methoxybenzylamine (449 mg), triethylamine (0.45 ml+0.89 ml) and (2S)-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]-l-(L-prolyl)pyrrolidine hydrochloride (1.18 g) as obtained by treating (2S)-1-[N-(t-butoxycarbonyl)-L-prolyl]-2-[1-hydroxy-2-(4-methoxyphenoxy) ethyl]pyrrolidine obtained in Example 22-A) with 4N hydrochloric acid/1,4-dioxane, there was obtained 661 mg of the title compound.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].[O:8]1[CH2:12][CH2:11][N:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]([CH:17]=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1>O1CCCC1>[O:8]1[CH2:12][CH2:11][N:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[C:18]2[CH2:19][CH2:20][N:21]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:22][CH2:23]2)=[CH:24][CH:25]=1
Reactant: C(=C1CCNCC1)c1ccc(C2=NCCO2)cc1
Reactant: C#CCCC(=O)O
Solvent: C1CCOC1
Product: C#CCCC(=O)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
356 mg (2.2 mmol) of N,N'-carbonyldiimidazole in 3 ml of tetrahydrofuran are added to 200 mg (2 mmol) of 4-pentynoic acid in 2 ml of tetrahydrofuran at ambient temperature. The mixture is stirred at 40° C. for 1 hour. 363 mg (1.5 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]piperidine are then added and the mixture is stirred at 40° C. for a further 2 hours. The reaction solution is then evaporated down and the residue is purified by column chromatography (Silica gel; ethyl acetate). 320 mg (66% of theory) of the title compound of melting point 118° C. are obtained.
Reaction SMILES: [ClH:1].OS(O)(=O)=O.[Na+].[Cl-].[CH3:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:19])=[C:16]([OH:18])[CH:17]=1)=[O:11].O[C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O>C(OCC)(=O)C>[Cl-:1].[OH:18][C:16]1[CH:17]=[C:12]([CH:13]=[CH:14][C:15]=1[OH:19])[C:10]1[CH:9]=[CH:23][C:22]2[C:25](=[CH:26][C:27]([OH:29])=[CH:28][CH:21]=2)[O+:11]=1
Reactant: Cl
Reactant: CC(=O)c1ccc(O)c(O)c1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1ccc2ccc(-c3ccc(O)c(O)c3)[o+]c2c1
Reaction time: 1 h
Yield: 75 %

Procedure:
At 0° C., hydrochloric acid (generated by dropwise addition of H2SO4 to NaCl) was bubbled in a two-necked flask containing 12 g (0.079 mol) of 3,4-dihydroxyacetophenone, 10.88 g (0.079 mol) of 2,4-dihydroxybenzaldehyde and 100 ml of ethyl acetate distilled beforehand. The product started to precipitate after 30 minutes. The bubbling was continued for another 1 hour and then the reaction was stopped. The solution was kept at −18° C. for 3 days and then it was filtered. The filtrate was evaporated and it was taken up in ether; the product precipitated. It was separated from the ether, dissolved in hot methanol and then it was added slowly to an equivalent volume of acetone. The solution was placed in a refrigerator and the product started to precipitate. After filtration, the filtrate was evaporated, dissolved in a minimum of methanol and then ether was added until a precipitate appeared. The procedure was thus repeated several times until precipitate no longer appeared. The purity of the 3′,4′,7-trihydroxyflavylium chloride precipitate thus obtained with a yield of 75% was checked by HPLC (high-performance liquid chromatography).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:31].O1CCOCC1>C(Cl)Cl>[ClH:31].[F:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(S(C)(=O)=O)cc2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl 4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step C product, 1.13 g, 2.56 mmol) was dissolved in DCM (20 ml) and HCl in dioxane (4 M solution, 9.60 ml, 38.4 mmol) was added. The mixture was stirred at RT for 1 h. The solvents were evaporated to afford 0.97 g of the desired product (100%) which will be used without further purification. LC/MS (m/z): 378 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)occ1OCc1ccccc1
Yield: 56.9 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (7-07) (20.0 g, 56.92%) was synthesized as a brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (20.0 g, 86.58 mmol) and 4-chloro-benzenesulfonyl chloride (6-07) (45.67 g, 216.45 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:33]=[CH:32][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]=4[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.O>O1CCOCC1>[CH:22]1[C:23]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][C:21]=1[C:19]([N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:14]2[C:5]([C:3]([NH:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:4])=[CH:6][CH:7]=[C:8]2[CH2:9]1)=[O:20]
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc2c(c1)Cc1ccccc1-2)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc3c(c1)Cc1ccccc1-3)C2
Temperature: 25 °C

Procedure:
A solution of 0.7 g (0.0014 mol) of 2,2,2-trichloro-1-[10-(9H-fluorene-2-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Step B and 0.30 g (0.0028 mol) of 3-aminomethylpyridine in 25 mL of 1,4-dioxane was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and poured into 75 mL of water with stirring. The precipitate was collected, washed with water, and recrystallized from ethanol to provide the title compound, m.p. 116-119° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[CH:28]([N:31]=[C:32]=O)([CH3:30])[CH3:29].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>ClCCl>[CH:28]([NH:31][C:32]1[O:21][C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:27]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:26]=[CH:25][CH:24]=2)=[N:22][N:23]=1)([CH3:30])[CH3:29]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Reactant: CC(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(NC(C)C)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 21 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (300 mg, 0.780 mmol) obtained in Step 2 of Example 56 was dissolved in dichloromethane (16 mL), and the mixture was stirred at room temperature for 14 hours after adding isopropyl isocyanate (0.092 mL, 0.936 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Using the resulting residue, (S)-5-[3-(5-isopropylamino-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (74.0 mg, 21%) was obtained in the same manner as in Step 3 of Example 52.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][S:26][C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])=[CH:35][C:29]=4[N:28]=3)[C:19]=2[Cl:43])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N.C(#N)C>ClCCl>[N:12]1([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][S:26]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([O:36][C:37]([F:41])([F:42])[CH:38]([F:39])[F:40])=[CH:35][C:29]=4[N:28]=3)=[O:9])[C:19]=2[Cl:43])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(Cl)c1N1CCCCC1
Agent: N
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cnc(CS(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(Cl)c1N1CCCCC1

Procedure:
m-Chloroperbenzoic acid (0.75 g total) in dichloromethane (40 ml) was added to a solution of 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylthio)-5-(1, 1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole (1.5 g) in dichloromethane (30 ml) at -40° to -50° over a period of 2.5 hours. After a further 0.5 hour ammonia was passed through the solution and the precipitate filtered off and washed well with dichloromethane. The filtrates were evaporated under reduced pressure to give an oil which, on treatment with acetonitrile, gave 2-(4-piperidino-3-chloro-5-methyl-2-pyridylmethylsulphinyl)-5-(1, 1,2,2-tetrafluoroethoxy)-(1H)-benzimidazole, 0.77 g. m.p. 155°-56° (dec).