Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[OH:17][C:18]1[C:19]([C:28](Cl)=[O:29])=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2>ClC1C=CC=CC=1.CN(C=O)C>[OH:17][C:18]1[C:19]([C:28]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3=[N:6][C:7](=[O:9])[N:8]=[C:4]3[CH:3]=2)=[O:29])=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: O=C(O)c1cc2ccccc2cc1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: O=C1N=c2ccc(NC(=O)c3cc4ccccc4cc3O)cc2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
75.0 g (0.5 mol) of 5-aminobenzimidazolone and 41 g of anhydrous sodium acetate are initially introduced into 700 ml of N,N'-dimethylformamide and 776.8 g of 3-hydroxy-2-naphthoyl chloride (from 99.0 g (0.52 mol) of 3-hydroxy-2-naphthoic acid) in chlorobenzene are metered in at 5°-10° C. in the course of 30 min. After addition is complete, the mixture is subsequently stirred at 20° C. for 3 h, warmed to 50° C. and filtered. The filter cake does not filter off with suction very well (suction time: 14 h). For purification, the filter cake is taken up in 1 ml of methanol, the mixture is stirred and filtered off with suction, and the filter cake is washed with 250 ml of methanol and subsequently several times with a total of 1 l of boiling water. After drying, 130.3 g of 3-hydroxy-N-benzimidazolon-5-yl-2-naphthamide are obtained; this corresponds to 81.7% of theory.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:42][CH:43]([F:45])[F:44])=[C:19]([C:21]2[C:25]([NH:26][C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[N:34][C:33]=34)=[O:28])=[CH:24][N:23]([CH2:38][C:39](O)=[O:40])[N:22]=2)[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:42][CH:43]([F:45])[F:44])=[C:19]([C:21]2[C:25]([NH:26][C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[N:34][C:33]=34)=[O:28])=[CH:24][N:23]([CH2:38][C:39]([N:5]3[CH2:6][CH2:7][N:2]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:4]3)=[O:40])[N:22]=2)[CH:20]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CCOC(=O)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a white solid. LCMS (Method 20) [M+H]+=617.2, RT=2.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[N:31]=[C:30]([CH2:32][OH:33])[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:15]1([NH:14][C:12](=[O:13])[C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([CH2:32][OH:33])[N:31]=4)=[CH:23][CH:22]=3)[CH:10]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: OCc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CO)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
3 -{[4-(hydroxy)benzoyl]amino }-N-cyclopropyl-4-methylbenzamide (100 mg, 0.323 mmol), [6-(bromomethyl)pyridin-2-yl]methanol (71 mg, 0.355 mmol) and potassium carbonate (49 mg, 0.355 mmol) were mixed in acetonitrile (3 mL) and the reaction was stirred at room temperature for 16 h. The reaction was then heated at 100° C. in the microwave for 10 mins. Water (10 mL) was added and the mixture was extracted with DCM (3×15 mL). The organic layers were combined and evaporated to give a white solid which was triturated with DCM to give the title compound as a white solid (80 mg, 58%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.6S (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 4.59 (s, 2H), 5.24 (s, 2H), 7.16 (d, 2H), 7.32 (d, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (d, 2H), 8.36 (d, 1H), 9.82 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:15](=[O:17])[C@H:10]([CH2:11][C:12](=[O:13])[OH:14])[NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)c1ccccc1
Reaction time: 7 h
Yield: 64.2 %

Procedure:
The procedure of Example 9 was followed excepting that: the quantity of N-benzoyl-L-aspartic acid was 2.85 g (10 mmol) and of the L-phenylalanine methyl ester was 2.69 g (15 mmol), in place of polyethylene glycol 600, polyethylene glycol 200 was used, the reaction time was 7 hours. N-benzoyl-L-aspartyl-L-phenylalanine methyl ester was obtained in the yield of 64.2%.
Reaction SMILES: [C-:1]#[N:2].[K+].O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25]Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]1[CH2:25][C:1]#[N:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 80 %

Procedure:
A mixture of 4.57 g (70.2 mmol) of potassium cyanide and 10 ml of water is heated to reflux. When the potassium cyanide has dissolved, 17 g (54 mmol) of the chloride obtained in Step b dissolved in 10 ml of ethanol are added slowly. When the addition is complete, the mixture is heated under reflux for 3 hours. After evaporation of the solvent, the mixture is taken up in chloroform and washed with water until the pH is neutral. The chloroform phase is dried over magnesium sulfate, filtered and evaporated off. The resulting residue is crystallised from hexane and yields 13.2 g of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH:10][C:18]([NH:17][CH3:16])=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CN(N)c1cccc(OC)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NN(CC(=O)OC)c1cccc(OC)c1

Procedure:
A solution of methyl [1-(3-methoxyphenyl)hydrazino]acetate (1.6 g) and methyl isocyanate (0.9 ml) in acetonitrile (20 ml) was heated under reflux for 1 h. The solvent was removed in vacuo and the residue was treated with ether to give the title compound (1.8 g) as a solid, m.p. 145°-146°.
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH3:26][C:25]1[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[N:4]([N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:27]=4)[CH:9]=3)[CH:12]=2)=[O:19])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (120 mg, 0.333 mmol) in N,N-dimethylacetamide (5 mL) was added propionylchloride (29.2 μL, 0.336 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (101 mg, 73%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.O.NN>C(O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:14]=3[C:13](=[O:15])[C:12]=2[CH:11]=1
Reactant: Cn1ncc2[nH]c3ccc(Cc4ccccc4N4C(=O)c5ccccc5C4=O)cc3c(=O)c21
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4N)cc3c(=O)c21
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of 2-{2-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]phenyl}-1H-isoindole-1,3(2H)-dione (EXAMPLE 25, step 2, 242 mg, 0.558 mmol) and hydrazine hydrate (0.14 ml, 2.8 mmol) in ethanol (10 ml) was refluxed for 18 h. After cooling to room temperature, the mixture was evaporated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with methanol/dichloromethane (1:20) to give 139 mg (82%) of 7-(2-aminobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one. 80 mg of this compound was treated with methanolic hydrochloric acid and the mixture was evaporated to give a yellow solid. This was washed with diisopropyl ether to give 78 mg of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH2:13])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>N1C=CC=CC=1>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NS(C)(=O)=O
Reaction time: 16 h

Procedure:
To 4.54 g (15 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylaniline in 25 ml pyridine, add 1.94 g (17 mmole) methanesulfonyl chloride. After 16 hours, pour onto 200 ml H2O and filter the solid. Recrystallize from Et2O-hexane to obtain the product; m.p. 109°-110° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][CH2:3]1.O.NN>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(N2CCC3(CCCN3C)C2)ccc1N
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A mixture of 160 mg of 1-methyl-7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane, 301 mg of hydrazine hydrate and 27 mg of 10% palladium-on-carbon in 30 ml of ethanol is heated at 80° C. (bath) for 2 h. The mixture is filtered and the filtrate is concentrated under vacuum, so as to obtain 141 mg of 4-(1-methyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)aniline in the form of a brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([C@H:17]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[O:28][CH3:29])[CH3:18])[CH2:16][O:15]1>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:15])([C@H:17]([N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[O:28][CH3:29])[CH3:18])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Product: COc1ncnc2c1ncn2[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 77.4 %

Procedure:
Using 1H-1,2,4-triazole (74 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-9-(9H)-purinyl]ethyl]oxirane (183 mg), Compound 47 (171 mg) was obtained as colorless prisms by the same was as in Example 1.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[Si:12](Cl)([C:15](C)(C)C)([CH3:14])[CH3:13]>C1COCC1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: OCCCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,7-heptandiol (44 mmol) in THF (15 mL) is cooled to 0° C. and treated with sodium hydride (44 mmol) followed by tert-butyldimethylsilyl chloride (44 mmol). The reaction mixture is stirred at room temperature overnight. Concentration in vacuo and flash chromatography affords 7-trimethylsiloxy-1-heptanol . To a solution of 7-trimethylsiloxy-1-heptanol (11.6 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 7-trimethylsiloxy-1-heptyl triflate (50) which is used without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][S:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][S:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 83.4 %

Procedure:
Methyl 2-{[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (0.137 g, 0.296 mmol) was dissolved in a mixture of acetonitrile/water (1/1, 4 ml), lithium hydroxide (0.014 g, 0.591 mmol) was added. The reaction was performed in an single node microwave oven (5 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The waterphase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation and gave 0.111 g of 2-{[2-(4-{2[-benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]-thio}benzoic acid (yield 83.5%).
Reaction SMILES: Br[CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[N-:13]=[N+:14]=[N-:15].[Na+].CCOC(C)=O>CN(C=O)C>[N:13]([CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCC1(c2ccc(I)cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC1(c2ccc(I)cc2)CC1
Yield: 80.1 %

Procedure:
Part A. 1-(1-Bromomethylcyclopropyl)-4-iodobenzene (2.0 g, 5.97 mmol) and NaN3 (1.0 g, 15.38 mmol, 2.6 eq) were stirred in DMF (10 mL) overnight. Analytical LC-MS showed completion of the reaction. EtOAc was added to the solution. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated to give 1-(1-azidomethyl-cyclopropyl)-4-iodobenzene (1.43 g, yield: 80%). The azide (1.40 g, 4.68 mmol) and PPh3 (1.84 g, 7.02 mmol, 1.5 eq) were stirred in THF (10 mL) at RT for 40 min. H2O (2 mL) was added, and the solution was stirred at 50° C. for 6 h. LC-MS showed completion of the reaction. The mixture was extracted with Et2O (2×). The aqueous layer was basified with 50% NaOH, extracted with CH2Cl2 (2×), washed with H2O, brine, dried over MgSO4, and concentrated to give 1-(4-iodophenyl)cyclopropyl methylamine (0.98 g, yield: 75%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([NH:13][C@H:14]1[C@@:23](C(=O)C2C=CC=CC=2)([OH:24])[C@:22](C(=O)C2C=CC=CC=2)([OH:33])[C@@H:21]([CH2:42]O)[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]>COCCOCCOC.C[O-].[Na+].CO>[C:10]([NH:13][C@H:14]1[C@@H:23]([OH:24])[C@H:22]([OH:33])[C@@H:21]([CH2:42][F:7])[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=CCO[C@H]1O[C@H](CO)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Product: C=CCO[C@H]1O[C@H](CF)[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of (diethylamino)sulfur trifluoride (0.5 mL) in dry diglyme (2mL) was added a solution of allyl 2-acetamido-3,4-di-benzoyl-2-deoxy-α-D-mannopyranoside, prepared as described above, (100 mg) in dry diglyme (3 mL) at room temperature, and the reaction mixture was stirred for one hour at room temperature and three hours at 40° C. After the starting material was consumed, the reaction mixture was poured onto ice-water and extracted with ethyl acetate. The extract was dried, concentrated, and the residue was applied to silica gel chromatography. After the impurity was eluted with hexane, the product was eluted with ether to give the fluorinated product in 89 percent yield. The product was then dissolved in 5 mL of 1N sodium methoxide in methanol to remove benzoyl group. After 20 minutes, Dowex 50W X-8[H+ ] was added to neutralize the reaction mixture. The resin was filtered and the filtrate was concentrated to give allyl 2-acetamido-2,6-dideoxy-6-fluoro-α-D-mannopyranoside in 99 percent yield. The product (50 mg), 1.2 equivalents of palladium (II) acetate, and 2.5 eq of sodium acetate in 95 percent acetic acid (5 mL) were stirred at 50° C. for 18 hours, and the solvent was removed under vacumn. The residue was applied to silica gel chromatography, eluted with ethyl acetate/methanol (2/1) to obtain 2-acetamido-2,6-di-deoxy-6-fluoro-α-D-mannopyranoside in 73 percent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: C=Cc1ccccc1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(C=Cc2ccccc2)c1OC
Temperature: 0 °C
Yield: 53.7 %

Procedure:
A mixture of 500 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)pyrimidine-2,4-diamine, 1.53 g of styrene, 1.46 g of triethylamine and 31 mg of palladium-(II) acetate in 25 ml of dioxan is held at reflux under argon for 14 hrs. The mixture is poured on to ice-water, adjusted to pH 5 to 7 with 3N aqueous hydrochloric acid and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol 97:3. 252 mg (53%) of 5-(3,4-dimethoxy-5-styryl-benzyl)pyrimidine-2,4-diamine are isolated as an orange solid. M.p.226°.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15]([O:17][CH3:18])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.O.[NH2:30][NH2:31].C([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)C>[CH2:22]([O:21][C:19](=[O:20])[NH:1][CH:2]([C:15]1[O:17][CH:18]=[N:30][N:31]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: NN
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nnco2)ccc1O
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (4.0 g, 10.39 mmol) in ethanol (100 ml), hydrazine monohydrate (6.4 ml, 103.9 mmol) was added at room temperature. The mixture was stirred overnight and evaporated under reduced pressure to remove the solvent. The thus obtained residue was mixed with ethyl orthoformate (100 ml) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol) at room temperature. The mixture was stirred for 1.5 hours and mixed with 1N HCl (100 ml). The mixture was stirred for 20 min., and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.34 g, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: Cc1cc(N)nc(C)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)nc(C)n1

Procedure:
To a suspension of 1.2 g of 4-amino-2,6-dimethylpyrimidine in 30 ml of dry acetonitrile with stirring was added 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was stirred for two hours at ambient temperature, allowed to stand for sixteen hours and the desired product, which had precipitated, was removed by filtration and washed with butyl chloride to yield 2.4 g, m.p. 125°-127°. The product showed absorption peaks by Nuclear Magnetic Resource at 4.0, 2.62 and 2.9 ppm; consistent for the product.