Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH2:7]Br.O>CS(C)=O>[Br:13][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][C:1]#[N:2])=[C:5]([F:4])[CH:12]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Sodium cyanide (1.37 g, 28.00 mmol) was added to a stirred solution of 2-fluoro-4-bromo benzyl bromide (5.0 g, 18.66 mmol) in dry DMSO (60 mL) at ambient temperature under nitrogen. The reaction was stirred for 4 h at ambient temperature then poured into H2O (150 mL) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the intermediate title compound as a brown oil (3.85 g, 96%). Electrospray mass spectrum: M=213, M+2=215
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=O)=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29].CCCCCCC>ClCCl.CCOC(C)=O>[OH:29][CH2:28][C:27]([NH:26][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)=[O:10])([CH3:31])[CH3:30]
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a suspension of mono-methylterephtalate (360 mg, 2.0 mmol) in dichloromethane (10 mL) under N2 was added 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in one portion. The mixture was stirred at RT for 18 h. 2-Amino-2-methyl-1-propanol (232 mg, 2.6 mmol) was added as a solution in dichloromethane (1 mL) and stirring was continued for another 3 h. The reaction was quenched by pouring onto saturated aqueous NaHCO3 (50 mL). After extraction with dichloromethane (3×50 mL), the combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (using a gradient of eluents; 7:3 to 1:1 heptane:EtOAc) gave the title compound (100 mg, 20% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([OH:12])[C:10]([I:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)cc(O)c1I
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)c(I)c(O)c1
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 3-amino-5-hydroxy-4-iodo-benzoic acid (0.20 g, 0.72 mmol) in methanol (5 mL) was added conc. sulfuric acid (0.20 mL, 0.035 g, 0.36 mmol) and the reaction mixture heated to reflux. After 2 h, the reaction mixture was poured on ice, the pH adjusted to 9 by addition of a sat. solution of sodium hydrogencarbonate and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (1:1) providing 0.07 g (33%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([CH:13]([OH:16])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH:13]([O:16][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(F)cc1[N+](=O)[O-])C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
To 14.8 g (47.3 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid in 90 ml dimethylformamide were added at 0° C. 8.26 g (189 mmol) sodium hydride (55%). The suspension was stirred for 2 hours and then 10.4 ml (94.6 mmol) 2,5-difluoro-nitrobenzene in 10 ml dimethylformamide were added. After stirring overnight the mixture was poured under cooling on aqueous 2M citric acid solution. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane (3:7) yielded 12.9 g (61%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid as orange solid, MS m/e (%): 453.0 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:4][C:3]=1[OH:20].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>O1CCCC1.CO>[CH2:21]([NH:23][C:24](=[O:25])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:4][C:3]=1[OH:20])[CH3:22]
Reactant: CCN=C=O
Reactant: Cc1ccn2cc(CCc3ccc(N)c(O)c3)nc2c1
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(CCc2cn3ccc(C)cc3n2)cc1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (20.0 g) and ethyl isocyanate (7.7 ml) in a mixture of tetrahydrofuran (200 ml) and methanol (200 ml) was stirred for 2.5 hours at ambient temperature. Evaporation of the solvent gave a residue, which was triturated with ethyl acetate to give a precipitate. The precipitate was collected by filtration and dried to give 2-[2-{4-(3-ethylureido)-3-hydroxyphenyl}ethyl]-7-methylimidazo[1,2-a]pyridine (17.86 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1O>>[F:18][C:14]1[C:13]2[O:6][C:4]([C:3]3[C:2]([NH2:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[N:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(F)c1O
Reactant: Nc1ncccc1C(=O)O
Product: Nc1ncccc1-c1nc2cccc(F)c2o1
Temperature: 200 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
A mixture of 2-aminonicotinic acid (9.4 g), 2-amino-6-fluoro-phenol (8.65 g) and polyphosphoric acid (90 g) was stirred at 200° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, quenched with water and basified with sodium hydroxide solution 6N until pH 12 to give a solid which was collected by filtration and dried under vacuum; The resultant product was diluted in dichloromethane/methanol and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated to dryness to give 3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (7.5 g) as a solid. NMR Spectrum: (DMSOd6) 6.76 (dd, 1H), 7.33-7.46 (m, 2H), 7.66 (bs, 2H), 7.68 (dd, 1H), 8.26 (dd, 1H), 8.30 (dd, 1H); Mass spectrum: M+H+ 230.
Reaction SMILES: [N:1]1([N:14]=[C:15]([CH3:17])[CH3:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[BH4-].[Na+]>CO>[N:1]1([NH:14][CH:15]([CH3:17])[CH3:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)=Nn1cnc2cnc3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Nn1cnc2cnc3ccccc3c21
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A solution of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (3.48 g, 15.5 mmol) in 75 mL of methanol was cooled in an ice water bath. The solution was treated over 5 min with sodium borohydride (2.94 g, 77.6 mmol). After 1 h, the reaction mixture was quenched with 20 mL of saturated NH4Cl solution and then concentrated under reduced pressure to yield a brown soild. The solid was partitioned between 80 mL CHCl3 and 20 mL saturated NaHCO3 solution and the phases were separated. The organic portion was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown solid. The solid was purified by chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) to give 1.28 g of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine as a tan foam.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:48][CH2:47][CH2:46][C:45]([OH:44])=[O:49])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 100 and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.96 (s, 1 H), 7.88 (br.s, 1 H), 7.12-7.35 (m, 8 H), 7.02 (m, 4 H), 6.89 (m, 4 H), 4.04 (m, 4 H), 3.22 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.37 (m, 5 H), 2.05 (m, 2 H), 1.76 (m, 2 H); MS (APCI) m/z 630 (M+H+).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[CH:10]([OH:11])[O:9][C@H:8]([CH2:12][OH:13])[C@@H:7]([O:14][C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H:6]1[OH:26])=[O:3].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1>[As](C)(C)(=O)[O-]>[OH:11][CH:10]1[O:9][C@H:8]([CH2:12][OH:13])[C@@H:7]([OH:14])[C@H:6]([OH:26])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: C[As](C)(=O)[O-]
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
Initial velocities of the enzyme reaction were determined by measuring the rate of LacNAc formation with a slight modification of the assay by Pierce et al. [Pierce et al., Anal. Biochem., 102:441 (1980)]. All the reactions were carried out in 100 mM cacodylate buffer (pH 7.5) with fixed concentrations of Mn2+ (9.3 mM) and UDP-Gal (0.1 mM; 58.5 cpm/pmol of UDP-14C-Gal) in 100 mL of solution. The reaction was initiated by the addition of GalT (0.05 U, 120 mg protein; from Sigma) and permitted to stand at 20° C. for 30 minutes. Nonspecific hydrolysis of UDP-Gal was measured by the control reaction in the absence of GalT. The reaction was stopped by passing through a column of QAE-Sephadex (700 mL), and eluted by gentle air pressure to remove the unreacted UDP-Gal. The reaction vial was rinsed twice with 400 mL of water each and passed through the resin column. The filtrates were collected and directly transferred into a scintillation vial. The scintillation fluid was added to the vial, and then radioactivity was counted by a liquid scintillation counter. The data were analyzed by a double reciprocal plot to obtain Km (1.5 mM for GlcNAc) [a value of 1.3±1 mM was reported in Palcic et al., Carbohydr. Res., 159:315 (1987)] and Ki (0.46±0.06 mM) for UDP. Similarly, IC50 value of UDP for GalT was determined using different concentration of UDP.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]COCCOC)=[C:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>CO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCOc1ccc(-c2cccc(F)c2)cc1-c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(-c2cccc(F)c2)cc1-c1ccc(C(F)(F)F)nc1
Yield: 81.7 %

Procedure:
A solution of 5-(3′-fluoro-4-((2-methoxyethoxy)methoxy)-[1,1′-biphenyl]-3-yl)-2-(trifluoromethyl)pyridine (1.61 g, 3.82 mmol) in methanol (100 mL) and 1.0 M aqueous hydrochloric acid (50 mL) was stirred at 60° C. for 2 days. The cooled reaction mixture was concentrated under reduced pressure to remove methanol, and the resulting aqueous suspension partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The organic phase was separated, washed with water (75 mL) and saturated brine (75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a cream solid. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 50% ethyl acetate (containing 2% methanol) in hexanes to give 3′-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)-[1,1′-biphenyl]-4-ol (1.04 g, 81% yield) as a white crystalline solid.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:16][CH:15]2[C:10]([NH2:17])([CH2:11][CH:12]=[CH:13][CH2:14]2)[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[CH3:25]COCC>>[ClH:1].[CH3:25][NH:17][C:10]12[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]([CH3:2])[CH2:16][CH:15]1[CH2:14][CH:13]=[CH:12][CH2:11]2
Reactant: CC1CC2CC=CCC2(N)c2ccccc21
Reactant: CCOCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: CNC12CC=CCC1CC(C)c1ccccc12
Yield: 81 %

Procedure:
A solution of the compound from Example 36 (0.65 g, 2.4 mmol) was reduced in a suspension of lithium aluminum hydride in ether as described in Example 33. A solution of the free amine in diethyl ether was treated with isopropanolic HCl to give the title compound (0.51 g, 81%), mp 248°-249° c.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[CH:9]([CH2:10][CH2:11][CH3:12])[O:8]2)=[O:6])[CH2:3][CH2:2]1.[N-:13]=[N+:14]=[N-:15].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[N:13]([CH:9]([CH2:10][CH2:11][CH3:12])[CH:7]([OH:8])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6])=[N+:14]=[N-:15]
Reactant: CCCC1OC1C(=O)NC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC(N=[N+]=[N-])C(O)C(=O)NC1CC1
Temperature: 65 °C
Yield: 60.3 %

Procedure:
A flask equipped with an overhead stirrer, thermometer and reflux condenser was placed under a nitrogen atmosphere then charged with the epoxide of Example 5 (20.0 g, 118 mmol), sodium azide (NaN3; 31.0 g, 473 mmol), magnesium sulfate (MgSO4; 14.0 g, 118 mmol) and methanol (MeOH; 200 mL). The mixture was heated to 65±5° C. for 2 hours then cooled to 25±5° C. and filtered through a pad of Celite 545. The solvent was removed under reduced pressure resulting in a thick oil which was taken up in IPAc (250 mL) then washed with water (3×250 mL). The organic phase was dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (15.1 g, 60%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15]1(B(O)O)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1>>[C:15]1([C:12]2[CH:13]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Product: Nc1ccc(CN2CCOCC2)cc1C1=CCCCC1

Procedure:
This compound was prepared from 4-morpholin-4-ylmethyl-phenylamine by brominating according to the procedure in Example 33, step (b), followed by Suzuki coupling to 1-cyclohexen-1-yl-boronic acid according to the procedure in Example 1, step (e). Mass spectrum (ESI, m/z): Calcd. for C17H24N2O, 273.2 (M+H). found 272.7
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:17]([O:19]CC)=O)[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([S:56]([NH2:59])(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1>C1COCC1.O.CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:17]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([NH2:59])(=[O:57])=[O:58])[CH:51]=2)=[O:19])[N:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1nc(C(C)(C)C)nn1Cc1ccccc1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)Nc2cccc(S(N)(=O)=O)c2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
A suspension of ethyl 5-tert-butyl-2-benzyl-2H-1,2,4-triazole-3-carboxylate (0.10 g 0.35 mmol) and LiOH.H2O (29 mg, 0.70 mmol) in THF (1 mL) and H2O (1 mL) was stirred at room temperature 2 h. The solvent was evaporated under vacuum, and to the residue was added DMF (2 mL) and HATU (0.13 g, 0.35 mmol). The reaction was stirred for 3 min, then 3-amino-benzenesulfonamide (60 mg, 0.35 mmol) was added. The reaction was stirred for 3 h, diluted with water, and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-5% MeOH-CH2Cl2) to obtain 5-tert-butyl-2-benzyl-N-(3-(aminosulfonyl)phenyl)-2H-1,2,4-triazole-3-carboxamide (16 mg, 11% yield). LC/MS: m/z 414.3 (M+H)+ at 3.46 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH2:10][NH:11][C@H:12]([CH3:27])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([O:25]C)=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[Si:1]([O:8][C@H:9]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH2:10][NH:11][C@H:12]([CH3:27])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Cc1ccc2[nH]c(C(=O)O)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylate (Preparation 12, 0.30 g, 0.59 mmol) in 1,4-dioxane (10 ml) was treated with a solution of sodium hydroxide (59 mg, 1.46 mmol) in water (1 ml) and the resulting mixture left to stir at room temperature for 30 minutes. After this time the reaction mixture was heated to 90° C. for 30 minutes and then cooled to room temperature. The solvent was removed in vacuo and the residue re-dissolved in water (20 ml) and pH adjusted to 7 by addition of 2N Hydrochloric acid. The solid that formed was filtered off, solubilised in a mixture of dichloromethane and methanol (20 ml 90:10 by volume), dried (magnesium sulphate) and the solvent removed in vacuo to give the title compound as a pale orange foam.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]2[C:3]=1[C:4](=N)[NH:5][C:6]2=[NH:29].[ClH:31].[CH2:32]([NH:39][C:40]1[S:41][CH2:42][C:43](=[NH:45])[N:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:31].[NH:29]=[C:6]1[C:7]2[C:3](=[C:2]([CH3:1])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:4](=[C:42]2[S:41][C:40]([NH:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:44][C:43]2=[NH:45])[NH:5]1
Reactant: Cc1c2c(c(-c3ccccc3)c(-c3ccccc3)c1-c1ccccc1)C(=N)NC2=N
Reactant: N=C1CSC(NCc2ccccc2)=N1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: Cc1c2c(c(-c3ccccc3)c(-c3ccccc3)c1-c1ccccc1)C(=N)NC2=C1SC(NCc2ccccc2)=NC1=N

Procedure:
Using a procedure similar to that described in Example 9, part B above but substituting 4-methyl-5,6,7-triphenyl-1,3-diiminoisoindoline and 2-benzylamino-4-imino-2-thiazoline hydrochloride for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-4-methyl-5,6,7-triphenyl-3-(2-benzylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2ccc3ccccc3c2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc2cc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)ccc2c1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-naphthyl)-oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-naphthyl)oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 131-132° C.
Reaction SMILES: [NH:1]([CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]=1[C:15]([OH:17])=O)[C:2]([NH2:4])=[O:3].Cl.[NH2:19][CH:20]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:21]1=[O:22]>N1C=CC=CC=1>[O:22]=[C:21]1[CH:20]([N:19]2[C:15](=[O:17])[C:7]3[C:8](=[CH:12][CH:13]=[CH:14][C:6]=3[CH2:5][NH:1][C:2]([NH2:4])=[O:3])[C:9]2=[O:11])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NC1CCC(=O)NC1=O
Reactant: NC(=O)NCc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 34.7 %

Procedure:
A mixture of 3-ureidomethyl-phthalic acid (1.5 g, 6.1 mmol) and α-amino-glutarimide hydrochloride (1.0 g, 6.1 mmol) in pyridine (15 mL) was refluxed for 5 hours. The mixture was concentrated and the residue was stirred with water (20 mL). The solid was slurried with hot methanol to give [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 36%): mp 292-294° C.; 1H NMR (DMSO-d6) δ 2.04-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.83-2.98 (m, 1H), 4.61 (d, J=6.1 Hz, 2H, CH2), 5.11-5.18 (m, dd, J=5.3 and 12.5 Hz, 1H, CH), 5.71 (s, 2H, NH2), 6.57 (t, J=6.0 Hz, 1H, NH), 7.70-7.87 (m, 3H, Ar), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.92, 38.66, 48.82, 121.63, 126.95, 131.50, 133.32, 134.61, 141.06, 158.65, 167.04, 167.57, 169.82, 172.76; Anal. calcd. for C15H14N4O5: C, 54.44; H, 4.27; N, 16.96. Found: C, 54.47; H, 4.17; N, 16.76.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)[CH2:11][C:10](=O)[C:9]2=[O:25])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=3)[CH:11]=[C:10]([NH:34][C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:26])[C:9]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(OC(F)(F)F)c2)N(c2ccc(Br)cc2)C1=O
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Product: C[C@@H](NC1=C[C@@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(Br)cc2)C1=O)c1ccccc1

Procedure:
Dissolve (±)-1-(4-bromo-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (14.6 g, 35.2 mmol) in dichloromethane (35 mL). Add (R)-(+)-α-methylbenzylamine (6.8 mL, 52.8 mmol) and stir overnight at ambient temperature. Concentrate the reaction mixture under reduced pressure and purify by silica gel chromatography (ethyl acetate-hexane) to yield (S)-1-(4-bromo-phenyl)-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one-eluting first (6.6 g, 36%): MS (m/z): 517.0 (M+1). RP HPLC: Tr=5.53 min (Method 3) and eluting second (R)-1-(4-bromo-phenyl)-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (5.8 g, 32%): MS (m/z): 517.0 (M+1). RP HPLC: Tr=5.44 min. (Method 3)