Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-:26])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Oc3ccncc3)cccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of Example 136 A (6.62 g 29.9 mmol) in dichloromethane (40 ml) is treated with m-chloroperbenzoic acid, 80% strength (7.10 g; 32.9 mmol), stirred at room temperature for 24 h and then heated to reflux for a further 2 h. The reaction mixture is washed twice with satd aqueous NaHCO3 solution. The combined aqueous phases are extracted with dichloromethane and the combined dichloromethane phases are dried (Na2SO4) and concentrated in vacuo. The residue is crystallized from dichloromethane/petroleum ether.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:22]([NH:10][C:9]([NH2:11])=[NH:8])([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxane (20 ml) is added to a solution of guanidine hydrochloride (0.96 g, 10 mmol) and sodium hydroxide (0.8 g, 20 mmol) in water (10 ml) and the resulting mixture is cooled to 0° C. Benzyloxycarbonyl chloride (1.1 ml, 7.7 mmol) is added dropwise with vigorous stirring over a period of 10 min. After the addition is completed, the ice-bath is removed and stirring is continued for 1 h at room temperature. The mixture is concentrated in vacuo to one third of its original volume and extracted three times with ethyl acetate (20 ml each). The combined extracts are washed with brine (20 ml) and dried with anhydrous sodium sulfate. After filtering and removal of the solvent under reduced pressure N-Cbz-guanidine (1.31 g, 88%) is obtained as a white powder: mp: 120-122° C.; 1H NMR (360 MHz, DMSO-d6) δ 7.35-7.25 (m, 5H), 6.88 (br s, 4H), 4.95 (s, 2H); Electrospray-MS m/e 194 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3cc(-c4ccccc4)nn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-5-phenylpyrazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])=[CH2:10]>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][CH:5]=2)([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Yield: 76 %

Procedure:
Example 11 was repeated except that the amount of the aniline hydrochloride was changed to 0.26 g (0.02 mole of catalyst per mole of the p-isopropenyl phenol monomeric unit). After the reaction, the reaction mixture was analyzed by gas chromatography. It was found that 17.3 g (yield 76%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane and 1.4 g of bisphenol A were formed.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and-saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (532 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:36]=[CH:35]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:37]6[N:36]=[CH:35][N:34]([CH3:33])[CH:38]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1cnc(C2(N)CC2)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.07 g, 1.1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Later water was added and organic layer was separated. The organic layer was washed with water and the crude product was purified by Prep. HPLC. Yield: 24.69 mg (10%) 1HNMR (400 MHz, CDCl3): δ 1.39 (s, 4H), 2.30 (s, 3H), 2.99-3.01 (d, J=4.6 Hz, 3H), 3.81 (s, 3H), 4.04 (s, 3H), 5.90 (s, 1H), 6.87 (s, 1H), 7.16-7.25 (m, 3H), 7.24 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.65 (s, 1H), 7.98-7.99 (m, 3H), 8.29 (s, 1H), 8.95 (s, 1H). LCMS: (ES+) m/z=553.2 (M+H). Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 ML/Min
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:23][NH:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 7 °C
Yield: 34.4 %

Procedure:
Phenylmaleic anhydride (30 g, 0.17 mol), sodium acetate trihydrate (28 g, 0.21 mol) and hydrazine monohydrate (10 ml, 0.21 mol) were heated together at reflux in 40% acetic acid (600 ml) for 18 h. The mixture was cooled at 7° C. for 2 h, then filtered. The solid was washed with diethyl ether and dried in vacuo to give 11 g (34%) of the title compound: 1H NMR (250 MHz, DMSO-d6) δ 7.16 (1H, br s), 7.44 (5H, m), 7.80 (2H, br s); MS (ES+) m/e 189 [MH+].
Reaction SMILES: C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3:22].[CH2:23]1[CH2:61][CH2:60][N:59]([OH:62])[C:57](=[O:58])[CH2:56][CH2:55][C:53](=[O:54])[NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][N:46]([OH:63])[C:44](=[O:45])[CH2:43][CH2:42][C:40](=[O:41])[NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([OH:64])[C:31](=[O:32])[CH2:30][CH2:29][C:27](=[O:28])[NH:26][CH2:25][CH2:24]1>C(OCC)(=O)C.O>[CH2:23]1[CH2:61][CH2:60][N:59]([O-:62])[C:57](=[O:58])[CH2:56][CH2:55][C:53](=[O:54])[NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][N:46]([O-:63])[C:44](=[O:45])[CH2:43][CH2:42][C:40](=[O:41])[NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([O-:64])[C:31](=[O:32])[CH2:30][CH2:29][C:27](=[O:28])[NH:26][CH2:25][CH2:24]1.[Fe+3:22]
Reactant: O=C1CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(=O)N([O-])CCCCCNC(=O)CCC(=O)N([O-])CCCCCNC(=O)CCC(=O)N([O-])CCCCCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5.29 g (15 mmol) of iron(III) acetylacetonate in 300 ml of ethyl acetate is added to a suspension of 5.26 g (10 mmol) of desferrioxamine E in 500 ml of water, and the mixture is efficiently stirred for 5 hours at room temperature. The aqueous phase is then extracted repeatedly with ethyl acetate and then lyophilised to give ferrioxamine E.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ncc(Cl)cc1Oc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
5-chloro-3-phenoxypyridin-2-amine (8.493 g, 38.490 mmol) and benzoyl isothiocyanate (6.9096 g, 42.339 mmol) were placed in THF (200 mL) and stirred at room temperature for 2 hours. THF was removed. A suspension was made by adding Hexanes:EtOAc (9:1). The suspension was filtered and the solid was washed with hexanes then dried to afford the title compound (13.752 g, 93.1% yield) as a yellow solid. 1H NMR (d6-DMSO) δ 12.35 (s, 1H), 11.84 (s, 1H), 8.34 (d, 1H), 7.95 (d, 2H), 7.66 (t, 1H), 7.53 (t, 2H), 7.44 (m, 3H), 7.24 (t, 1H), 7.18 (m, 2H); Mass spectrum (apci) m/z=383.1 (M+H).
Reaction SMILES: [OH-:1].[K+].C[CH:4]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5]CS([O-])(=O)=O>C1(C)C(C)=CC=CC=1>[CH2:5]([O:1][CH2:5][CH2:4][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(C)CCS(=O)(=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCCCOCCCCCC
Yield: 14.3 %

Procedure:
A mixture of 0.67 g (120 mmol) of powdered KOH in 20 ml of dry xylene was heated to reflux and ~10 ml of xylene was removed by distillation. To this stirred mixture was added a solution of 400 mg (1.49 mmol) of [1α,2β(Z),3β,4α]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester prepared as described in U.S. Pat. No. 4,143,054 in 6 ml of xylene. Approximately 10 ml of xylene was removed by distillation to afford a clear solution with a gummy precipitate adhering to the magnetic stirring bar. To this mixture was added a solution of 1.45 g (7.5 mmol) of crude 2-methyl-hexylmesylate in 4 ml of xylene. This caused the gummy precipitate to break up to form a somewhat gelatinous reaction mixture. The mixture was refluxed for 21/4 hour. The cooled reaction mixture was partitioned between 20 ml each saturated NH4Cl and EtOAc. The aqueous layer was acidified to pH=3.5 and then extracted with three 20 ml portions of EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was treated with excess ethereal CH2N2. The crude product was purified by flash chromatography on 35 g of silica gel using 4:1 hexane/ether as eluant. Fractions 15-20 were concentrated to give 320 mg of title ether (58%). Fractions 23-27 afforded 100 mg of the n-hexyl ether related to title ether (19%). (Apparently, the commercial 2-methyl-hexanoic acid which was the precursor to the mesylate employed was contaminated with ~10% hexanoic acid) and fractions 21-22 gave 70 mg (13%) of a mixture of these two ethers.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][CH3:30])[C:26]([Cl:31])=[CH:25][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:31][C:26]1[C:27]([NH:29][CH3:30])=[N:28][C:23]([NH:1][C:2]2[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=2)=[N:24][CH:25]=1
Reactant: CNc1nc(Cl)ncc1Cl
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C(F)(F)F)c(C(=O)N3CCOCC3)cc2OC)ncc1Cl
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2,5-dichloro-N-methylpyrimidin-4-amine (55 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 36 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-10% EtOAc in iso-hexane) gave (4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (11 mg, 8%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=446 at 3.60 min. 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.40 (br s, 1H), 7.90 (s, 1H), 6.76 (s, 1H), 5.59 (q, J=4.9 Hz, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 1H), 3.82-3.69 (m, 3H), 3.62-3.56 (m, 2H), 3.26-3.20 (m, 2H), 3.13 (d, J=4.9 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][C:38]([CH3:44])([CH3:43])[C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>>[Cl:40][C:39]([Cl:42])([Cl:41])[C:38]([O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36])([CH3:44])[CH3:43]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1)C(Cl)(Cl)Cl

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trichloro-1,1-dimethyl-ethyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.89 (m, 6H), 2.02-2.08 (m, 4H), 3.00-3.10 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.10-4.16 (m, 2H), 5.05-5.09 (m, 1H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.40 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=576.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22](Cl)(Cl)=[S:23].[OH-].[Na+]>O1CCCC1>[N:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1)=[C:22]=[S:23]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Triethylamine (4.5 mL, 65.4 mmol) was added to a tetrahydrofuran (500 mL) solution of 4-morpholin-4-ylmethyl-phenylamine (F45-000, 5.16 g, 26.8 mmol). After cooling in ice cold, thiophosgene (2.45 mL, 32.1 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydroxide was added until the reaction mixture became basic. The reaction mixture was extracted with ethyl acetate, washed with water and then washed with saturated sodium chloride. The extract solution was dried over anhydrous sodium sulfate, and then sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain a red syrup like substance. The syrup like substance was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain 4-(4-isothiocyanatobenzyl)-morpholine (F45-00, brown oil, 5.72 g, 91%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.[I:21]I>C1COCC1>[F:13][C:14]1[C:19]([I:21])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: II
Reactant: Cc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cnc(F)c(I)c1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A solution of diisopropylamine (7.0 mL, 50.0 mmol) in THF (100 mL) at −78° C. was treated with 2.5M n-butyllithium in hexanes (20 mL, 50.0 mmol), stirred for 15 minutes, treated dropwise with a solution of 2-fluoro-5-methylpyridine (5.55 g, 50.0 mmol) in THF (20.0 mL), stirred for 4 hours, treated slowly with a solution of iodine (12.7 g. 50.0 mmol) in THF (50 mL), quenched with water, and extracted with diethyl ether. The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/diethyl ether to provide 7.24 g (61%) of 2-fluoro-3-iodo-5-methylpyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][CH:38]([CH3:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:40]([CH2:39][CH:38]([CH3:44])[CH3:37])(=[O:42])=[O:41])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (300 mg, 0.61 mmol) was dissolved in dry tetrahydrofuran (20 ml) (using gentle heating), a solution of 2-methyl-1-propanesulphonyl chloride (50 mg, 0.32 mmol) in dry tetrahydrofuran (2.5 ml) added and the mixture stirred at room temperature for 18 hr under a nitrogen atmosphere. A solution of triethylamine (100 mg, 0.98 mmol) and 2-methyl-1-propanesulphonyl chloride (50 mg, 0.32 mmol) in dry tetrahydrofuran (5 ml) was added and the resulting mixture stirred for a further 5 hr. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (97:3), to give the product as a foam (117 mg). MS: 611 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([OH:19])[CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:19][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[CH2:29][CH:28]=[CH2:27]
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Yield: 41.4 %

Procedure:
Next, 10.4 g of the 4,4'-dinitro-2-hydroxybiphenyl thus obtained was dissolved in 95 mL dry acetone. 5.52 g of potassium carbonate and 7.56 g of 4-bromo-1-butene were added, and the resulting mixture was heated under reflux for 71 hours. Workup by the usual methods gave 5.20 g of 2-(3-butenyloxy)-4,4'-dinitrobiphenyl as a light yellow powder.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10]([NH2:12])=[S:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:10]([NH2:12])=[S:11]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=S
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)C(N)=S
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[1-(4-hydroxynonyl)thioureido]heptanoic acid (10.3 g., 0.03 mole) (Example 3) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Then acetic acid is added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution, brine, then dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[1-(4-hydroxynonyl)thioureido]heptanoate as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[C:19](O)=[O:20])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:25]>>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[C:19]([Cl:25])=[O:20])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarboxylic acid (75 mg, 0.246 mmol) was dissolved in anhydrous MC (5 ml), SOCl2 (0.58 g, 4.92 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.