Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:11]3[N:16]=[N:15][N:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[C:12]=3[N:13]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:11]3[N:16]=[N:15][N:14]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[C:12]=3[N:13]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCNCC3)c2n1
Yield: 85.4 %

Procedure:
Reaction of the above carbamate (158 mg, 0.270 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3-(4-piperidinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (112 mg, 85%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.83 (dd, J=8.4, 0.4 Hz, 1H), 7.46 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 4.87 (tt, J=11.7, 4.2 Hz, 1H), 4.80 (br s, 2H), 4.15 (br s, 2H), 4.07 (s, 3H), 3.92 (d, J=15.0 Hz, 4H), 3.34 (m, 2H), 2.88 (dt, J=12.7, 2.5 Hz, 2H), 2.38 (dq, J=12.0, 4.2 Hz, 2H), 2.18 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1.[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH:20][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:31][CH:32]=2)[CH:11]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
A solution of 0.80 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of N,N-dimethylformamide were added 1.31 g of 4-benzyloxybenzyl chloride and 1.18 g of sodium hydrogencarbonate, and the mixture was stirred at 90° C. for 2 hours. Chloroform and water were added to the reaction solution, and the chloroform extraction was conducted. The organic layer was washed with water, concentrated, and purified through silica-gel column chromatography to give 0.434 g of N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[NH:6][C:7]=1[CH2:8]Cl.[NH:12]=[C:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.[O-]CC.[Na+]>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[NH:6][C:7]=1[CH2:8][N:14]1[CH2:15][CH2:16][CH2:17][C:13]1=[NH:12]
Reactant: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Reactant: N=C1CCCN1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: N=C1CCCN1Cc1[nH]c(=O)[nH]c(=O)c1Cl
Yield: 74.9 %

Procedure:
A solution of 5.0 g of 5-chloro-6-chloromethyl-uracil, 6.14 g of 2-iminopyrrolidine and 5.24 g of sodium ethoxide in N,N-dimethylformamide (50 ml) was stirred at room temperature for 14 hours. A crystallized matter was collected by filtration and then suspended in 30 ml of water. After the suspension was neutralized with acetic acid and then washed, an insoluble matter was collected by filtration and then dissolved in 60 ml of 1N hydrochloric acid. Activated carbon was added to the resultant solution, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue so obtained was washed with ethanol and collected with filtration, whereby 2.68 g of the title compound were obtained (yield: 38%).
Reaction SMILES: [H][H].[C:3]([CH2:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])#[N:4]>N.CO.[Rh]>[CH:18]1[N:17]=[CH:16][NH:15][C:14]=1[CH2:13][C@H:9]([NH:8][C:6]([CH2:5][CH2:3][NH2:4])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Rh]
Agent: N
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 90 °C

Procedure:
A 1-litre pressure autoclave was initially charged with 1.76 g of Rh/C (0.4 mol % pure Rh, based on reactant used) in a mixture of 94.2 g of ammonia solution (25% in H2O) and 62.8 g of methanol. The autoclave was closed, and the contents were heated to 90° C. and the autoclave was pressurized with 40 bar of hydrogen. A, solution of 20.0 g (0.09 mol) of (S)-2-(cyanoacetyl-amino)-3-(1H-imidazol-4-yl)propionic acid (prepared according to Example 3) in a mixture of 94.2 g of ammonia solution (25% in H2O) and 62.8 g of methanol was then metered in over the course of one hour. After further reaction at 90° C. for one hour, the reaction mixture was cooled to room temperature. The autoclave was depressurized and the catalyst was filtered off via activated carbon. An in-process HPLC analysis showed that the clear greenish reaction solution (326.2 g) contained 5.74% (m/m) carnosine, corresponding to a selectivity of 92% for complete conversion. The reaction mixture was then concentrated to approx. 60 g in a rotary evaporator. Dropwise addition of 174 g of ethanol caused precipitation of a white solid which was filtered off and dried at 50° C./20 mbar.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>[OH-].[Na+]>[C:7]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)c1ccccc1)C(=O)O

Procedure:
L-alanine (17.8 g., 0.2 mole) was dissolved in 2N-sodium hydroxide solution (120 ml.) with cooling to 0°-5° C. Benzoyl chloride (30.0 g., 0.22 mole), followed by 2N-sodium hydroxide (120 ml.), were then added to the solution in ten equal and alternate portions with vigorous intermittent shaking and ice cooling. The mixture was continually maintained at an alkaline pH. After completion of the addition, the mixture was shaken for 15 minutes at room-temperature. The clear solution obtained was acidified with concentrated hydrochloric acid to pH2 whilst ice cooling to give N-benzoyl L-alanine as a solid (27.8 g.), m.p. 137°-139° C.
Reaction SMILES: Cl[C:2](=[C:7]([Cl:12])[C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4].II>>[Cl:12][CH:7]([CH2:2][C:3]([F:4])([F:5])[F:6])[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Agent: II
Product: FC(F)(F)CC(Cl)C(F)(F)F
Temperature: 250 °C
Reaction time: 15 h
Yield: 40.7 %

Procedure:
2,3-Dichlorohexafluorobut-2-ene (100 g) and iodine (55 g) were added to a 400 mL shaker tube. The tube was sealed, cooled, evacuated, and charged with 1500 psi of hydrogen at room temperature. The tube was then heated to 230° C. for 1 hour, 250° C. for 2 hours, and 260° C. for 15 hours. The tube was then cooled to room temperature, vented, and opened. The purple liquid was washed with water and then analyzed by GC/IR. Analysis of the washed liquid showed that it contained about 84% 2-chloro-1,1,1,4,4,4-hexafluorobutane, about 13% 2,3-dichloro-1,1,1,4,4,4-hexafluorobutane and about 1% 1,1,1,4,4,4-hexafluorobutane. The liquid was distilled on a concentric tube column yielding 35 g (41% isolated yield) of 2-chloro-1,1,1,4,4,4-hexafluorobutane (HCFC-346mdf) as a clear liquid with a b.p. of 50.9-51.4° C. 1H NMR (CHCl3 as internal standard): 4.4 ppm, complex, 1H; 2.9 ppm, complex, 1H; 2.7 ppm, complex, 1H. 19F NMR (CCl3F) as internal standard): 64.7 ppm, t, 1F; -76 ppm, d, 1F. GC/IR showed an identical spectrum to an authentic sample.
Reaction SMILES: [NH2:1][CH:2]([CH:4]([NH2:6])[CH3:5])[CH3:3].[CH:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[C:11]=2[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[NH2:1][CH:2]([CH3:3])[CH:4]([NH:6][S:17]([C:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:19])[CH3:5]
Reactant: CC(N)C(C)N
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Product: CC(N)C(C)NS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 79.9 %

Procedure:
In 100 ml of chloroform was dissolved 12.9 g of 2,3-diaminobutane and to the solution was added dropwise 10 ml of a chloroform solution containing 4.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and the reaction mixture solution was washed with water and dried with anhydrous sodium carbonate. The chloroform was distilled therefrom under reduced pressure, and the residue thus obtained was subjected to a column chromatography [silica gel: 160 g; solvent: chloroform] to give 3.92 g of N-(2-amino-1-methylpropyl)-5-isoquinolinesulfonamide in a yield of 80%.
Reaction SMILES: [NH2:1]CC1C=CC=CN=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29])C1C=CC=CC=1.O>C1C=CC=CC=1.C(OCC)C>[F:35][C:34]([F:37])([F:36])[CH2:33][O:32][C:26]1[CH:25]=[CH:24][CH:23]=[CH:31][C:27]=1[C:28]([NH2:1])=[O:29]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: NC(=O)c1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.2 g (0.0299 mole) of 2-aminomethylpyridine and 12.1 g (0.114 mole) of sodium carbonate in 100 ml of benzene is added dropwise a solution of 9.8 g (0.0285 mole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 30 ml benzene. The mixture is stirred for about 16 hours at room temperature. Water and diethyl ether are added. The ether layer is separated, washed with water, then with saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, and the magnesium sulfate is removed by filtration. The filtrate is evaporated to provide a white solid, 5-benzyloxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxybenzamide. The infrared and nuclear magnetic resonance spectra of this product are consistent with the assigned structure.
Reaction SMILES: CC([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1>>[CH3:27][S:26][C:22]1[N:23]=[C:24]([C:7]2[CH:8]=[CH:9][NH:5][CH:6]=2)[CH:25]=[CH:20][N:21]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Product: CSc1nccc(-c2cc[nH]c2)n1
Yield: 95 %

Procedure:
The title compound was prepared analogous to Step A of Method B, starting from [1-[tris(1-methylethyl)silyl]-1H-pyrrol-3-yl]-boronic acid and 4-chloro-2-methylsulfanyl-pyrimidine. Under the reaction conditions, the triisopropylsilyl protecting group was cleaved. Yield: 95%.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][O:24]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[C:8]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].N[C@]1(O)[C@@H](O)[C@H](C(Cl)O)O[C@@H]1N1C2C=C(Cl)C=CC=2N=C1>CO.C(O)C.O>[C:1]([NH:4][C:5]1[N:9]([C@H:10]2[O:22][C@@H:21]([CH2:23][OH:24])[C@H:16]([OH:17])[C@@H:11]2[OH:12])[C:8]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:7]=2[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N[C@@]1(O)[C@@H](n2cnc3ccc(Cl)cc32)O[C@@H](C(O)Cl)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(=O)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.35 g, 0.75 mmol) in methanol (8 mL) and ethanol (8 mL) was combined with a solution of sodium carbonate (0.12 g, 1.1 mmol) in water (2 mL). The solution was stirred at rt for 24 h, then the methanol and ethanol were removed on the rotoevaporator. The solution was then extracted between ethyl acetate (2×150 mL) and saturated NaCl (20 mL). The organics were concentrated and purified by multiple cyclings on a chromatotron, fitted with a 2 mm rotor, using 1:10 methanol:dichloromethane to give a white solid (0.067 g, 0. 18 mmol, 23%); This material was identified by 1H NMR, MS and HPLC, it contained about 7% of 2-amino-5,6-dichloro-beta-L-ribofuranosyl-1H-benzimidazole by 1H NMR. HPLC showed two small (~5%) impurities.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Cl:15])=[C:10]([Br:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: Cc1noc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1Br
Yield: 25 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-5-chlorothiophene-2-sulphonyl chloride in 25% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 143-145° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=2[C:7]([O:9]CC)=O)[CH2:3][CH2:2]1.ClS([N:23]=[C:24]=[O:25])(=O)=O.C([O-])(=O)C.[Na+].CC(C)([O-])C.[Na+]>ClCCl>[CH:1]1([N:4]2[C:5]3[N:15]=[C:14]([S:16][CH3:17])[C:13]([F:18])=[CH:12][C:6]=3[C:7](=[O:9])[NH:23][C:24]2=[O:25])[CH2:2][CH2:3]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(F)c(SC)nc1NC1CC1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc2c(cc1F)c(=O)[nH]c(=O)n2C1CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
A solution of 4.1 g (15.2 mmol) of ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34) in 125 mL of dichloromethane is cooled to −20° C. and treated dropwise with 5.24 g (37 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at −20° C. for 3 hours and allowed to come to room temperature overnight. The mixture is recooled to −20° C. and treated with 6.8 g (80 mmol) of solid sodium acetate. After stirring for 1 hour without cooling, the solvent is removed in vacuo without heating. The residue is triturated with a saturated solution of sodium acetate in brine and extracted with ethyl acetate (3×75 mL). The combined organic layers are dried (MgSO4), filtered and evaporated in vacuo. The residue is suspended in 100 mL of tetrahydrofuran and treated with 3.6 g (32 mmol) of solid sodium tert-butoxide and stirred at room temperature for 36 hours. The solvent is removed in vacuo, the residue triturated with 100 mL of 0.1 M formic acid and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give a residue which is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane to give 0.75 g of the title compound, mp 220–222° C.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][N:23]2[NH:27][CH:26]=[CH:25][S:24]2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][N:23]4[NH:27][CH:26]=[CH:25][S:24]4)[CH:28]=[CH:29][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[5-(thiadiazol-2-ylcarbamoyl)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.79 min, MH− 394. NMR: δH [2H6]-DMSO 13.14, (1H, b), 9.24, (1H, s), 9.14, (1H, s), 8.86, (1H, t), 8.35, (1H, d), 8.25, (1H, s), 8.10, (1H, d), 7.82, (1H, d), 7.54, (1H, d), 3.21, (2H, t), 2.46, (3H, s), 1.07, (1H, m), 0.47, (2H, m), 0.27, (2H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[C:11](Cl)(Cl)=[O:12].[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][CH:16]1[CH2:21][CH2:20][N:19]([C:11]([O:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Cl
Reactant: Oc1n[nH]c2ccccc12
Reactant: CC1CCNCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1CCN(C(=O)Oc2n[nH]c3ccccc23)CC1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
300 mg (2.24 mmol) of 1H-indazol-3-ol were dissolved in 25 ml of THF and cooled to −20° C.: 1.3 ml (2.46 mmol) of phosgene in toluene (20 percent) were added dropwise and the reaction mixture was stirred for 90 min, during which it warmed to room temperature. The reaction mixture was concentrated and evacuated once again with a few ml of toluene. The residue was dissolved in 15 ml of THF, 265 μl (2.2 mmol) of 4-methylpiperidine were added dropwise and the mixture was stirred at room temperature for 3 h, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 347 mg (60%), M+H+: 260.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(O)CCC>O1CCOCC1>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:18]4[CH:19]=[C:20]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CCCCO
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
The mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.64 mmol, 1.0 equiv.), 3-aminobenzenesulfonamide (329 mg, 1.91 mmol, 3.0 equiv.), butan-1-ol (1 mL) and dioxane (0.5 mL) was stirred at 95° C. for 8 h. Then, the reaction mixture was cooled to room temperature and filtered. The residue was crystallized with methane/water/isopropyl ether to afford Compound 82 (7.7 mg, 3%). LC-MS (m/z): 372.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.62-0.63 (m, 2H), 0.88-0.92 (m, 2H), 1.82-1.86 (m, 1H), 6.06 (bs, 1H), 6.49 (bs, 1H), 7.39 (s, 2H), 7.52 (d, J=1.8 Hz, 2H), 7.97 (s, 3H), 10.02 (s, 1H), 10.45 (bs, 1H), 12.27 (bs, 1H).
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C@H:14]2[OH:46])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:60]1[C:65](=[O:66])[CH2:64][CH2:63][C:61]1=[O:62])=[N+](C)C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[O:62]=[C:61]1[CH2:63][CH2:64][C:65](=[O:66])[N:60]1[O:43][C:42](=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][C:37]([NH:36][CH2:35][CH2:34][O:33][C@H:15]1[O:16][C@H:17]([CH2:20][O:21][C@H:22]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]2[OH:24])[C@@H:18]([OH:19])[C@H:13]([O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C@@H:14]1[OH:46])=[O:45]
Reactant: O=C(O)CCCCC(=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCC(=O)ON1C(=O)CCC1=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoic acid (1.55 g, 2.294 mmol) in DMF (22 mL) at 0° C. was added TSTU (760 mg, 2.52 mmol) and DIPEA (0.52 mL, 2.98 mmol). After stirring at 0° C. for 1 hr, the reaction was quenched by the addition of TFA (371 μL, 4.82 mmol) and the resulting mixture was concentrated down to about 3 mL. The residue was transferred dropwise, via autopipette, to a tube containing anhydrous acetonitrile (45 mL). The white precipitate was collected through centrifugation (3000 rpm, 15 min, at 4° C.), washed with anhydrous AcCN (1 mL) and dried to yield the title compound. UPLC Method B: calculated for C30H48N2O21 772.27, observed m/e: 773.23 [M+1]; Rt=3.65 min. 1H NMR (D2O) δ 5.07-5.06 (1H, m), 4.84-4.83 (1H, m), 4.79-4.78 (1H, m), 4.06-4.01 (2H, m), 3.96-3.93 (2H, m), 3.87-3.83 (5H, m), 3.80-3.78 (1H, m), 3.75-3.69 (5H, m), 3.67-3.61 (4H, m), 3.57-3.52 (1H, m), 3.41-3.38 (2H, m), 2.91 (4H, s), 2.75-2.71 (2H, m), 2.29-2.25 (2H, m), 1.75-1.58 (4H, m).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][N:9]([C:20]([NH2:19])=[O:21])[CH2:8]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 72 h
Yield: 46.1 %

Procedure:
To a solution of 2.2 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine in 45 ml of methylene chloride and 45 ml of absolute ethyl alcohol was added 7 g. (0.066 mole) of nitrourea and the mixture was stirred at room temperature for 48 hr. The mixture was filtered. The filtrate was evaporated to dryness and the residue was partitioned between 75 ml methylene chloride and 75 ml water. The water layer was extracted three times with 50 ml of methylene chloride. The methylene chloride extracts were combined and evaporated to dryness. The residue was treated (washed) with a mixture of 1 ml methylene chloride and 20 ml of toluene and filtered. The precipitate was recrystallized from ethanol-water to give pale yellow crystals. The crystals were mixed with 2 ml of methylene chloride and 20 ml toluene and the mixture was heated on a steam bath for 2 hrs. The mixture was stored in a refrigerator for approximately 72 hrs. and filtered to give 1.2 g of the product as white crystalline needles, m.p. 151°-152° C.