Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]2[NH:9][C:8]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37]Br)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[N:7]([CH2:37][CH2:36][CH2:35][CH:32]3[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30][CH2:31]3)[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:37][CH2:36][CH2:35][CH:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:30][CH2:31]4)[C:10]=3[N:9]=2)=[CH:14][CH:15]=1
Reactant: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting mixture was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture 3-[1-(t-butoxycarbonyl)piperidin-4-yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined and washed with water (2×10 ml), and then brine (1×10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was further purified by flash chromatography. There is some substitution at the 7-position of the benzimidazole present, although the 4-substituted is the major isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1[C:14]([CH3:18])([CH3:17])[C:15]#[N:16].[C-:19]#[N:20].[K+]>CN(C)C=O>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1[C:14]([CH3:18])([CH3:17])[C:15]#[N:16])#[N:20]
Reactant: CC(C)(C#N)c1cc(Cn2cncn2)ccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cc(Cn2cncn2)ccc1C#N

Procedure:
A mixture of 2-[2-bromo-5-(1H-1,2,4-triazol-1-ylmethyl)-phenyl]-2-methylpropiononitrile (0.15 g), dimethylformamide (2 ml) and cuprous cyanide (0.09 g) was stirred and heated under reflux for 8 h. The cooled mixture was treated with aqueous potassium cyanide solution (10 ml) and the mixture was stirred for 10 minutes, then extracted three times with dichloromethane. The combined extracts were dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography, using methanol (2% by volume) in chloroform as eluant, to give 2-[2-cyano-5-(1H-1,2,4-triazol-yl methyl)phenyl]-2-methylpropiononitrile, characterised as the hydrochloride salt mp 159°-166°.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[CH:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:20]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C1CCCC1
Yield: 86.8 %

Procedure:
Using the method of Example 53, using 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6 mmol), cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) and triethyl amine (4.07 g, 40.3 mmol), overnight at RT giving the title compound (9.13 g, yield 87%). 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.11 (d, 1H, J=7.8 Hz), 7.24-7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96-2.87 (m, 1H), 1.74-1.45 (m, 8H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:10]([CH2:45][CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:29]3[CH2:35][CH:34]4[N:36]([CH2:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH:31]([CH2:32][CH2:33]4)[CH2:30]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[C:22]([O:27]C)[CH:21]=[CH:20][CH:19]=3)=[O:12])[CH3:9].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>>[CH2:45]([N:10]([CH2:8][CH3:9])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:29]3[CH2:30][CH:31]4[N:36]([CH2:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH:34]([CH2:33][CH2:32]4)[CH2:35]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[C:22]([OH:27])[CH:21]=[CH:20][CH:19]=3)=[O:12])[CH3:46]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(O)cccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a solution of the TFA salt of 6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 6e (55 mg, 0.086 mmol) in 1,2-dichloromethane (5 mL) at 0° C. was added a 1M solution of BBr3 (0.43 mL, 0.43 mmol). The mixture was allowed to stir for 2 h at rt. A saturated NaHCO3 solution was added, and the organic phase was separated. The aqueous phase was extracted with methylene chloride, and the combined organic phases were dried, filtered, and evaporated. The residue was purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield 23 mg (42.8%) of title compound 6-hydroxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 7e as a TFA salt and as a mixture of endo and exo isomers. MS m/z=512 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([CH2:9][C:10](=[O:35])[NH:11][C@@H:12]1[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]1NC(=O)C)[NH2:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:36])[C@H:7]([CH2:9][C:10](=[O:35])[NH:11][C@@H:12]1[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]1[O:36][C:6](=[O:5])[CH3:7])[NH2:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1NC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](NC(=O)C[C@H](N)C(=O)OC(C)(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-N-(2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl)-L-asparagine tert.-butyl ester (Cornpound 11) The N-Z-protected compound 7 (2.2 g) was hydrogenated in the presence of Pd/C and worked up as described above. Yield: 1.63 g. TLC analysis: Rf=0.47 (chloroform/methanol 6:1 )
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[NH:15]C(=O)N[C:12]1=[O:17].[OH-:18].[Na+]>>[NH2:15][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:17])=[O:18]
Reactant: O=C1NC(=O)C(c2ccc3ccccc3c2)N1
Reactant: [OH-]
Agent: [Na+]
Product: NC(C(=O)O)c1ccc2ccccc2c1

Procedure:
A solution of 5-(2-naphthyl) hydantoin (10g., 44.5 mmole) in 10% sodium hydroxide solution (50 ml.) was heated under reflux for 18 hours. The solution was cooled, filtered, diluted and treated with concentrated hydrochloric acid to bring the pH to 5.0. The resulting solid was filtered off washed with water and added to 5N-hydrochloric acid (2 L.). Insoluble material was filtered off and the filtrate was taken to pH 5.0 with 40% sodium hydroxide solution. On standing, the amino-acid crystallised out as platelets (3.92 g.) m.p. 238°-240°, λλmax. (pH 6.0 phosphate) 225 (ε 51,700), 276 (ε 3,520), 268 nm. (ε 3,420).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]([N+:25]([O-:27])=[O:26])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A mixture of 118.6 parts of methyl 4-(acetylamino)-2-ethoxybenzoate, 200 parts of acetic acid and 156 parts of acetic acid anhydride was stirred and heated to 50° C. After cooling to 15° C. (ice-bath) there were added dropwise 47.1 parts of fuming nitric acid 100% using a bromine funnel: an exothermic reaction occured. The temperature was kept at about 20° C. by cooling in an ice-bath. Upon completion, the temperature was allowed to rise to 40° C. and stirring was continued at this temperature for one hour. If necessary the whole was cooled with ice-water to keep the temperature at about 40° C. When the exothermic reaction was ceased, the whole was allowed to cool for one hour and was further cooled to 0° C. The reaction mixture was poured onto ice-water while stirring. Upon stirring for one hour, the precipitated product was filtered off and dissolved in 1950 parts of dichloromethane. The solution was washed twice with 500 parts of water, dried, filtered and evaporated. The residue was crystallized overnight at room temperature from 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 67.6 parts (47.9%) of methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate; mp. 110° C. (intermediate 32).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:18]2=[S:19])[CH:16]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C)C1=S
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5 -chloro-2-methylphenyl-isothiocyanate (9.18 g), triethyl amine (12 g) and chloroform (200 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl(2×200 ), then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethanol to give the tide compound (9.2 g) as a tan solid, m.p. 132°-134° C. Anal. Calcd. for C11H11 Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.79; H, 4.12; N, 10.73. Mass spectrum (EI, M.+) m/z 254/256.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:30]=[C:31]=[O:32])[CH2:28][CH3:29]>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:31]([NH:30][CH2:27][CH2:28][CH3:29])=[O:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCCN=C=O
Solvent: c1ccncc1
Product: CCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and n-propyl isocyanate (0.011 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in, the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.0 (dd), 158.3, 157.9 (dd), 151.1, 141.0, 138.9, 136.1, 135.0, 132.7, 132.1, 128.9, 127.4 (dd), 126.0 (dd), 122.5, 120.9, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 42.6, 24.4, 19.7, 11.6
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)#[N:2].[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F.[H-].[Na+]>CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:5]1[CH:6]=[CH:7][C:3]([C:1]#[N:2])=[CH:4]1
Reactant: N#Cc1cc[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccn(-c2ccc([N+](=O)[O-])cc2F)c1
Yield: 41.5 %

Procedure:
3-Cyanopyrrole (3.6 g, 39.1 mmol , CE Loader et al, Can. J. Chem., 1981, 59, 2673) and 3,4-difluoronitrobenzene (6.5 g, 40.9 mmol) were dissolved in DMF (50 ml) and cooled in an ice-bath. The mixture was stirred and sodium hydride (60% in oil, 1.6 g, 40 mmol) added over 20 minutes. After allowing the mixture to come to ambient temperature, it was heated to 650 for 1 hour. Solvent was evaporated, the residue triturated with water, and filtered. The crude solide was purified by flash chromatography on silica, eluting with dichloromethane. Relevant fractions were combined to give the title product (3.75 g), mp 117-119°.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[N:13]1([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:29]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([N:13]2[CH2:18][CH2:17][N:16]([CH:2]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:5][CH3:6])=[O:4])[CH2:15][CH2:14]2)=[CH:24][CH:23]=1)=[O:27]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Methyl α-bromo-α-phenylacetate (0.1 mole) was added dropwise to a stirring mixture of intermediate (10) (0.07 mole) and Na2CO3 (13 g) in DMF (300 ml). The mixture was stirred overnight. The solvent was evaporated. The residue was crystallized from methanol. The precipitate was filtered off and dried, yielding 30.2 g of methyl 4-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-α-phenyl-1-piperazineacetate (melting point 125° C.) identified as compound No. 52 in the following table F-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Br)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(F)c(Br)n1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A 50 mL round bottom flask equipped with a reflux condenser was charged with solid methyl 4-amino-6-bromo-5-fluoropicolinate (1.0 g, 4.02 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (1.227 g, 5.02 mmol), bis(triphenylphosphine)-palladium(II) dichloride (Pd(PPh3)2Cl2; 0.141 g, 0.201 mmol), and KF (0.467 g, 8.03 mmol). The reaction mixture was flushed with nitrogen, and then solvent (3:1 acetonitrile-water, 24 mL) was added. The reaction mixture was heated to reflux under nitrogen for 2 h. Upon cooling to room temperature, the product was filtered, washed with acetonitrile followed by water, and dried in a vacuum oven overnight to give the product (0.89 g) as an off-white solid: mp 204-206° C. An additional 0.29 g of product was isolated from the filtrate for a combined yield of 89%. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J=6.6 Hz, 1H), 7.46 (dd, J=8.5, 1.4 Hz, 1H), 7.30 (dd, J=8.4, 7.2 Hz, 1H), 6.71 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 3.31 (s, 4H); 13C NMR (101 MHz, DMSO-d6) δ 164.82 (s), 153.17 (d, J=249.5 Hz), 146.87 (d, J=254.3 Hz), 143.83 (dd, J=13.4, 3.8 Hz), 143.69 (d, J=4.3 Hz), 139.05 (d, J=10.6 Hz), 128.20 (d, J=3.2 Hz), 125.96 (d, J=3.4 Hz), 125.42 (d, J=3.6 Hz), 123.83 (dd, J=14.3, 3.1 Hz), 112.54 (s), 61.56 (s), 52.25 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.37 (d, J=26.0 Hz), −142.56 (d, J=26.3 Hz).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)(=O)=O)=CC=1.[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:28][C@@:26]1([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[C:59]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=2)[CH:58]=1)[OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[O:28][C@@:26]1([C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[C:59]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([O:71][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[CH:67][CH:66]=2)[CH:58]=1)[OH:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(OC2CCOC2)cc1

Procedure:
0.10 g tetrahydrofuran-3-yl toluene-4-sulphonate are added to a mixture of 0.24 g 1-(2,3,4,6-tetra-O-benzyl-(β-D-glucopyranos-1-yl)-3-(4-hydroxy-benzyl)-4-methyl-benzene and 0.13 g caesium carbonate in 2.5 ml of dimethylformamide. The mixture is stirred for 4 h at 65° C., before water is added. It is extracted three times with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is removed. The residue is purified through silica gel purified (cyclohexane/ethyl acetate 10:1->4:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:18]([O:31][CH3:32])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40].O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:18]([O:31][CH3:32])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27]([NH:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: COc1c(NC(=O)c2ccc(Cl)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Yield: 37 %

Procedure:
step 2—A solution of 312 (0.059 g, 0.1 mmol) and 2,2,2-trifluoroethylamine (0.5 mL) in NMP (1.0 mL) in a screw-capped test tube was heated to 100° C. After 18 h the solution was cooled to RT poured into H2O and extracted with EtOAc. The combined organics were washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane (6% to 60% EtOAc) to afford 0.029 g (37%) 6-(2,2,2-trifluoro-ethylamino)-pyridazine-3-carboxylic acid [5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-amide (314) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N+:9]([O-])[C:10]3[C:15]([C:16]=2[N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[C:21]1([N:27]=C=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[NH:27]([C:8]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:16]([N+:17]([O-:19])=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c[n+]([O-])c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(N2CCOCC2)c(Nc2ccccc2)nc2ccccc12

Procedure:
The 3-morpholino-4-nitroquinoline-N-oxide (3 g, 0.011 mol) was suspended in dimethylformamide (40 ml) and following addition of phenyl isocyanate (3.4 g, 0.029 mol), the mixture was added on an oil bath at 80°-90° C. for ca. 3 hours. The reaction mixture was totally charged into water and subjected to extraction with chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. After the chloroform was distilled off under vacuum, the residue was subjected to recrystallization with ethanol. The resulting crystal was recovered by filtration under vacuum to obtain 2-anilino-3-morpholino-4-nitroquinoline in an amount of 2.95 g (yield, 77%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].I[CH2:11][CH3:12]>CCCCCC.C1COCC1>[CH2:11]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:9])[CH3:12]
Reactant: OCCCCCO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
NaH (4.2 g, 0.11 mol) was washed with hexane and then suspended in dry THF (400 mL). Pentane-1,5-diol (10.4 g, 0.1 mol) in THF (50 mL) was added and stirred for 1 h at room temperature. Iodoethane (17.2 g, 0.11 mol) in THF (50 mL) was added and the mixture was refluxed for 48 h. After evaporation of the solvent, the residue was dissolved in EtOAc (300 mL). The organic phase was washed with water (2×50 mL), brine (50 mL), and dried (Na2SO4). The residue was purified by column chromatography on alumina with 10% 2-propanol in hexane, and then Kugelrohr distillation to give the title product (2) (9.4 g, 71%); bp 45° C.-46° C./0.005 torr; IR(neat): 3400 (broad) and 1115 cm-1 ; 1H NMR: 1.22 (t, 3H, J=6.8 Hz), 1.42 (m, 2H), 1.56 (m, 4H), 3.43 (t, 4H, J=5.8 Hz), 3.48 (q, 2H, J=6.8 Hz), and 3.58 ppm (b s, IH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10](OCC)(=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.04 g of (6-chloro-3-pyridazinyl)hydrazine was dissolved in 70 ml of ethanol; 8.6 ml of diethyl oxalate was added, followed by stirring at room temperature for 16 hours and subsequent refluxing under heating for 1 day. After cooling, the precipitated crystal was washed with diethyl ether and dried to yield 7.32 g of the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:12])[C:10]#[CH:11]>C(#N)C>[C:1]([NH:3][C:4](=[N:12][CH2:9][C:10]#[CH:11])[S:5][CH3:6])#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: C#CCN
Solvent: CC#N
Product: C#CCN=C(NC#N)SC
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A solution of dimethyl cyanodithioimidocarbonate (16.0 g; 0.109 mole) and propargylamine (6.03 g, 0.109 mole) in acetonitrile (320 ml) was stirred at reflux for 4 hours, then at ambient temperature for 12 hours. Workup gave 13.58 g (85%) of N-cyano-N'-(2-propyn-1-yl)-S-methylisothiourea; mp 160°-164°.