Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[C:9]#[CH:10])=[O:6])([CH3:4])[CH3:3].[N:23]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])=[N+:24]=[N-:25].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:2]([S:5]([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=1)[C:9]1[N:25]=[N:24][N:23]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:10]=1)=[O:6])([CH3:1])([CH3:3])[CH3:4]
Reactant: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Reactant: CC(C)(N=[N+]=[N-])C(=O)O
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C(=O)O)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reaction time: 24 h
Yield: 43.2 %

Procedure:
To a solution of 0.50 g (1.5 mmol) 2-methyl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]prop-2-ynyl}propane-2-sulfinamide in 3.0 mL water and 3.0 mL t-butanol was added 1.8 mL (1.5 mmol) 2-azido-2-methylpropanoic acid, 0.15 mL (0.15 mmol) 1.0M aqueous sodium ascorbate solution, and 15 μL (0.02 mmol) 1.0M solution of aqueous copper (II) sulfate. After 24 h at room temperature, the reaction mixture was quenched with water, acidified with 1N HCl, extracted three times with ethyl acetate, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-20% MeOH:CH2Cl2) afforded 0.30 g (44%) 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic acid. ES-MS [M+1]+=464.2.
Reaction SMILES: [CH2:1]1[O:22][P:20]([OH:23])(=[O:21])[O:19][C@H:3]2[C@@H:4]([OH:18])[C@H:5]([N:7]3[C:16]([Br:17])=[N:15][C:9]4[C:10]([NH2:14])=[N:11][CH:12]=[N:13][C:8]3=4)[O:6][C@H:2]12.C1N=C(N)C2N=CN([C@@H]3O[C@@H]4COP(O)(O[C@H]4[C@H]3O)=O)C=2N=1.C(O)(=O)C.C([O-])(=O)C.[BrH:54]>>[CH:12]1[N:11]=[C:10]([NH2:14])[C:9]2[N:15]=[CH:16][N:7]([C@@H:5]3[O:6][C@@H:2]4[CH2:1][O:22][P:20]([OH:23])([O:19][C@H:3]4[C@H:4]3[OH:18])=[O:21])[C:8]=2[N:13]=1.[Br:54][Br:17]
Reactant: Br
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Agent: CC(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Solvent: CC(=O)O
Product: BrBr

Procedure:
A key reagent in the preparation of many of the compounds according to the invention is 8-Br-cAMP. Up until now, reports in the literature only refer to small scale preparations (e.g. <100 mg) of this material using dilute (0.1M) solutions of cAMP in an acetic acid/acetate medium. Attempts to use similar dilute conditions in larger scale work resulted in problems due to the large volumes of solvent required. We have now found that the procedure may be scaled up using concentrated solutions of cAMP with a concentrated buffer to scavenge the HBr that is produced during the reaction of cAMP with bromine. By using concentrated cAMP solutions, a two-fold benefit is also achieved—the proportion of the 8-Br-cAMP product that is precipitated out as if forms is optimised (thus making product collection easier) and the cAMP(H) starting material contributes to the buffer system. Thus for example 0.2M cAMP(H) and 0.4M sodium acetate creates a buffer system equivalent to 0.2M NaOAc/AcOH with a pH which remains stable during the bromination at about 4.7.
Reaction SMILES: C1(N[C:8](=[O:16])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Br:15])C=CC=CC=1.[ClH:17].C(OCC)(=[O:20])C>>[ClH:17].[Br:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:8]([OH:16])=[O:20]
Reactant: O=C(Nc1ccccc1)c1ccncc1Br
Reactant: CCOC(C)=O
Agent: Cl
Product: O=C(O)c1ccncc1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an RBF equipped with a condenser and outfitted with a heating mantle was placed the N-phenyl-3-bromo-isonicotinamide (34 g, 0.123 mol) and 200 ml of 25% HCl. The reaction was left to stir for 3 days. The mixture was cooled to room temperature, and diluted with ethyl acetate. The aqueous layer was extracted and the two layers separated. To the aqueous layer, solid Na2CO3 was added until the pH˜4-5 and a dark oil layer appeared. This was then diluted and extracted with ethyl acetate. The two layers were separated and the aqueous layer was concentrated under reduced pressure to give an off-white solid. To this 100 ml of 2M HCl was added and the solids collected. The off-white solids were placed in a vacuum oven at 60° C. overnight. Yield: 22.4 g (76% th).
Reaction SMILES: [OH:1]C(COC1C=CC(C(O)=O)=CC=1)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>N1C=CC=CC=1.C(N)=O>[C:46]([NH:45][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)([NH:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(C(=O)O)cc2)CCN(CC(=O)O)CC1
Solvent: c1ccncc1
Solvent: NC=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of the gadolinium complex of 10-(2-hydroxy-3-(4-carboxyphenoxy)-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (500 mg, 0.72 mmol) in pyridine/formamide (1:1, 10 mL) was cooled to 0° C. with stirring. Dicyclohexylcarbodiimide (DCC, 149 mg, 0.72 mmol) and N,N-dimethylaminopyridine (DMAP, 20 mg, 0.16 mmol) were added. The resulting solution was stirred for 30 min at 0° C. A solution of dextran (MW 40,000; 1.0 g, 0.025 mmol) in formamide/pyridine (1:1, 30 mL) was prepared by gently warming a suspension of the polysaccharide. The dextran solution was added to the activated chelate and the mixture was stirred at 25° C. for 4 days. During this time a precipitate of dicyclohexylurea formed. The suspension was filtered and the polysaccharide was precipitated by dropwise addition of the filtrate into ethanol/ether (1:2, 300 mL). The suspension was stirred for 30 min then allowed to settle. The solvent was decanted off and the solid was isolated by filtration. The product was purified by GPC on a column of Sephadex G-25 eluted with distilled H2O. Fractions corresponding to the macromolecular component were collected, pooled and lyophilized. To ensure there were no small molecular components unremoved by GPC an analytical sample was prepared by ultrafiltration (Centrex MWCO 10,000) of an aqueous solution (500 μL) containing the product (300 mg). The retentate was collected and lyophilized giving a white pad (296 mg). The UV spectrum of an aqueous solution of this product (0.175 mg/mL) had an absorbance at 258 nm which confirmed the presence of the benzoic acid ester. The analytical sample contained 0.92% gadolinium, corresponding to approximately 3 mol Gd/mol dextran.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40].O>C1C=CC=CC=1>[CH3:23][C:22]1([C:19]2[CH:20]=[CH:21][C:16](/[CH:15]=[C:14](/[C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)\[CH3:25])=[CH:17][CH:18]=2)[O:40][CH2:39][CH2:38][O:24]1
Reactant: CC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C/C(=C\c1ccc(C2(C)OCCO2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
3.0 g of 4'-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-acetophenone (prepared as described in Example 22) dissolved in 40 ml of benzene are treated with a catalytic amount of p-toluenesulphonic acid and 0.6 g of ethyleneglycol and warmed in a Dean-Stark apparatus, the water formed being concurrently separated off. After heating under reflux for 2 days, the mixture is cooled down, introduced into ice/saturated sodium bicarbonate solution and exhaustively extracted with ether. The ether extract is washed twice with a saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure to remove the solvent. The oily residue is purified by adsorption on silica gel using hexane/ether (9:1) for the elution. The 2-methyl-2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-phenyl]-1,3-dioxolane obtained from the eluate melts at 122°-123° C. after recrystallisation from ether.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:12][CH2:11]1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]2[C:17](=[O:26])[C:18]3=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]3[C:20]2=[O:21])[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (60 g; 0.39 mol) was added in portions to a mixture of trans N-(4-hydroxycyclohexyl)phthalimide (D62, 95 g; 0.39 mol), imidazole (55 g; 0.78 mol), and DMF (200 mL) at 20-30° C. (internal, ice cooling). After stirring for 3 h more at 40° C. the mixture was partitioned between water/hexane. Drying and evaporation of the organic layer gave the title compound (92 g) crystallised from pentane.
Reaction SMILES: [N+]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10]2)=[N:5]1)([O-])=O.[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1.C(OCC)(=O)C>[N:16]1([CH2:22][CH2:23][NH:24][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=3)[NH:5][N:4]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc2cn([N+](=O)[O-])nc2c1
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(NCCN3CCOCC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,6-dinitro-2H-indazole (1 mmol) (prepared by nitration of 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596) in dry THF (4 mL) at 0° C., 2-morpholin-4-yl-ethylamine (2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The contents were diluted with ethyl acetate (20 mL), washed with water (2×10 mL), and brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield 3-(2-morpholin-4-yl-ethylamino)-6-nitro-1H-indazole as a brown solid, which was reduced to 3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-ylamine by hydrogenation following general procedure F.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.[C:26](O)(=[O:29])[CH2:27][OH:28].Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:27](=[O:28])[CH2:26][OH:29])=[CH:25][CH:24]=1
Reactant: O=C(O)CO
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CO)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To a stirred suspension of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (1.6 g, 3.9 mmol), glycolic acid (600 mg, 7.8 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 7.8 mmol) in CH2Cl2 (15 mL) was added Et3N (2.7 mL, 19.5 mmol). The resulting solution was then stirred at rt for 16 h. The resulting white suspension was partitioned between CH2Cl2 (600 mL) and satd. aq. NaHCO3 (100 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a white solid (853 mg, 55%). MS (ESI): mass calcd. for C21H21N3O3S, 395.13; m/z found, 396.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.38 (m, 1H), 7.32 (br m, 2H), 7.28 (m, 1H), 4.83 (br m, 0.5H), 4.21 (br d, J=14.5 Hz, 0.5H), 4.10-3.99 (br m, 2H), 3.80 (br d, J=11.7 Hz, 0.5H), 3.76 (d, J=13.8 Hz, 2H), 3.61 (br s, 1H), 3.50 (br s, 0.5H), 3.48-3.45 (m, 0.5H), 3.42 (br s, 0.5H), 3.39-3.35 (m, 0.5H), 3.23 (dd, J=9.2, 2.3 Hz, 0.5H), 3.01 (dd, J=9.7, 2.1 Hz, 0.5H), 2.90 (dd, J=9.8, 2.2 Hz, 0.5H), 2.81-2.77 (m, 0.5H), 2.58 (dd, J=9.7, 1.2 Hz, 0.5H), 2.07-2.01 (m, 0.5H), 2.00-1.96 (m, 0.5H), 1.80 (d, J=9.8 Hz, 0.5H), 1.70 (d, J=10.0 Hz, 0.5H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([O:19]C)[CH:12]=2)=[O:9])=[C:6]([NH:21][C@H:22]([C:24]2[N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:28](=[O:36])[C:27]3=[C:37]([CH3:40])[CH:38]=[CH:39][N:26]3[N:25]=2)[CH3:23])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:19])[CH:12]=2)=[O:9])=[C:6]([NH:21][C@H:22]([C:24]2[N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:28](=[O:36])[C:27]3=[C:37]([CH3:40])[CH:38]=[CH:39][N:26]3[N:25]=2)[CH3:23])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3cc(O)cc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 3 %

Procedure:
(S)-4-Amino-N-(3,5-dimethoxyphenyl)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (720 mg, 33% purity, 0.43 mmol) was treated with boron tribromide (1M in dichloromethane, 2.60 ml, 2.6 mmol) in dichloromethane (10 ml) according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 36 mg (3% yield) as a solid. Purity 99%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]([C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:15])[N:14]=1)[NH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:8][NH:7][C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:13]([CH3:15])[N:14]=1)=[O:3])[CH3:6]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Yield: 64.8 %

Procedure:
A solution of ethyl chloroformate (1.98 g) in methylene chloride (5 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.68 g) in methylene chloride (40 ml) under ice cooling in 15 minutes, and the reaction mixture was treated with a solution of triethylamine (1.8 g) in methylene chloride (10 ml) under ice cooling. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of water. The extract was washed with 5% hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was pulverized with diisopropyl ether. The resulting precipitates were collected by filtration, washed with water and dried to give 3-(2-ethoxycarbonylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.23 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1(C(OC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].[C-]#N>CS(C)=O.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14]
Reactant: COC(=O)C1(CCC2OCCO2)CCCCC1=O
Agent: [C-]#N
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCCC1CCC1OCCO1

Procedure:
The product of Example 102 was reacted with sod ,m cyanide (0.69 g, 14.1 mmoles) in 25 mL of DMSO at 160° C. for 12 hrs. The reaction mixture was then diluted to 700 mL with water and extracted with ethyl acetate/hexane (1:1). The solvent removed from the extracts to provide the title compound as oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:12])=[NH:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[N:12][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc2c(c1)OCO2
Product: NCc1c(N)nc(-c2ccc3c(c2)OCO3)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=388.2 (M+), was prepared from benzo[1,3]dioxole-5-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].[N:25]1([CH2:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O)[CH:29]=[CH:28][N:27]=[CH:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:25]1([CH2:30][C@@H:31]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20][CH3:21])=[O:19])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: COC(=O)c1cccc(SCc2c(O)ccc3c2CCCC3=O)c1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 94 %

Procedure:
Using the method in Example 154, this compound was prepared from methyl 3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfanylbenzoate (1.81 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) and purified by a silica-column (eluting with dichloromethane-MeOH 20:1) as a solid-foam, 2.56 g, 94% yield; mp 65° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O4S.0.5H2O:
Reaction SMILES: F[C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.CN1CC[CH:20](OC2C=CC(C#N)=CC=2C(F)(F)F)[CH2:19][CH2:18]1>>[CH:3]1([O:4][C:5]2[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:2]1
Reactant: CN1CCC(Oc2ccc(C#N)cc2C(F)(F)F)CC1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Product: CC(N)c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine, step B, starting from 4-[(1-methylpiperidin-4-yl)oxy]-3-(trifluoromethyl)benzonitrile. Yield 49 mg, 62% (oil) after column chromatography on silica gel (eluent: CHCl3/MeOH/conc.NH3, 80:20:1). MS (APCI) m/z 303 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23 (d, J=6.5 Hz, 3 H), 1.64-1.72 (m, 2 H), 1.86-1.92 (m, 2 H), 2.17 (s, 3 H), 2.21-2.27 (m, 2 H), 2.47-2.55 (m, partly overlapped with DMSO peaks, 2 H), 3.97-4.02 (m, 1 H), 4.55-4.60 (m, 1 H), 7.21 (d, J=8.9 Hz, 1 H), 7.55 (dd, J=8.7, 1.9 Hz, 1 H), 7.60 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])[CH:2]=[CH2:3].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[S:27](Cl)(=[O:29])=[O:28])=[C:21]([O:31][CH3:32])[CH:20]=1>>[CH2:15]([N:4]([CH2:1][CH:2]=[CH2:3])[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:27](/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=1[O:31][CH3:32])(=[O:28])=[O:29])(=[O:7])=[O:6])[CH:16]=[CH2:17]
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)/C=C/c1ccc(Cl)cc1OC
Yield: 50 %

Procedure:
The title compound was synthesized as described for Example 204 c) in 50% yield, starting from N,N-diallyl-4-aminopyridine-3-sulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride. Purification by column chromatography, using chloroform/methanol (98:2) as the eluent.
Reaction SMILES: N1(C2C=CN=CC=2)CCCC1.[O:12](C1C=CC(OCCO)=CC=1)C1C=CC=CC=1.FC1(F)CC1CC(O)=O.[CH:38]1([N:44]=[C:45]=[N:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH:47]1([NH:46][C:45]([NH:44][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:12])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Agent: O=C(O)CC1CC1(F)F
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C

Procedure:
0.1 g of 4-pyrrolidinopyridine and 2.53 g of 2-(4-phenoxyphenoxy)-ethanol are added to a solution of 1.5 g of 2-(2,2-difluorocyclopropyl)-acetic acid in 20 ml of methylene chloride, and the mixture is cooled to 0° C. At a temperature of from 0° C. to +5° C., a total of 2.5 g of N,N'-dicyclohexylcarbodiimide is added in portions, the ice-cooling is removed and the reaction mixture is allowed to warm to room temperature over a period of 5 hours with stirring. The N,N'-dicyclohexylurea obtained as precipitate is separated off and discarded. The supernatant solution is washed twice with 10 ml of water each time, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography on silica gel (eluant: hexane/ethyl acetate, 85:15), yielding pure 2-(2,2-difluorocyclopropyl)-acetic acid 2-(4-phenoxyphenoxy)-ethyl ester in the form of a yellowish oil having a refractive index of nD22 : 1.5309.
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CO>[N:10]1([C:4]2[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1nccnc1Cl
Reactant: C1COCCN1
Solvent: CO
Product: N#Cc1nccnc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 3-cyano-2-chloropyrazine (0.7 g, 5.0 mmol) in methanol (20 mL) was added morpholine (1.0 mL, 11.0 mmol) and the reaction was stirred at room temperature overnight. The solvent was removed in vacuo, then the residue was dissolved in diethyl ether. The precipitate was filtered off and the filtrate was concentrated under reduce pressure to give the title compound as an orange solid (0.95 g).