Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21]
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1F)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butylester (2.4 g; 7.73 mmol) was dissolved in methylene chloride. Trifluoroacetic acid (10 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 1.1 g of (2R)-3-(2-fluorophenyl)-N-methyl-2-(methylamino)-propionamide.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][O:16][C:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=[CH:19][N:18]=1.N1C=C(C)C=C(C)C=1.Cl>C(#N)C.CS(C)=O>[CH3:14][O:13][C:5]1[N:4]2[N:3]=[C:2]([NH:1][S:23]([C:22]3[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][C:21]=3[C:27]([F:30])([F:28])[F:29])(=[O:24])=[O:25])[N:10]=[C:9]2[C:8]([O:11][CH3:12])=[CH:7][N:6]=1
Reactant: COc1nccc(C(F)(F)F)c1S(=O)(=O)Cl
Reactant: COc1cnc(OC)n2nc(N)nc12
Agent: Cc1cncc(C)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nccc(C(F)(F)F)c1S(=O)(=O)Nc1nc2c(OC)cnc(OC)n2n1
Temperature: 40 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (19.5 g, 0.10 mol) and 2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonyl chloride (27.5 g, 0.10 mol) were combined in acetonitrile (35 mL). To this was added 3,5-lutidine (32 g, 0.30 mol), followed by DMSO (0.23 g, 0.0030 mol). A slight exotherm was noted (to about 30° C.) in the initial hours as the reaction slurry was stirred at ambient conditions for 17 hours. The mixture was then warmed to 40° C. and treated with 2 N HCl (140 mL). The new slurry was stirred while being allowed to cool to room temperature over one hour. The solids were isolated by filtration, washed with water, and dried under vacuum to afford 38 g of product as a solid assaying at 97 wt % (85% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Yield: 85.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.300 g; 0.82 mmol), LHMDS 1N in THF (0.9 mL; 0.9 mmol), 1-iodopropane (0.12 mL; 1.23 mmol) in DMF (3.3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.290 g (85%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:8]([OH:10])=[O:9])[CH3:7])=[O:4].[C:11]1(=[O:34])[N:15]([N:16]([C:21](=[O:32])[CH2:22][S:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C:18]([O-:20])=[O:19])[C:14](=[O:33])[CH2:13][CH2:12]1>O.C(O)C>[C:14]1(=[O:33])[N:15]([N:16]([C:21](=[O:32])[CH2:22][S:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C:18]([O-:20])=[O:19])[C:11](=[O:34])[CH2:12][CH2:13]1.[C:24]([S:23][CH2:22][C:21]([NH:1][CH2:2][C:3]([NH:5][C@@H:6]([C:8]([OH:10])=[O:9])[CH3:7])=[O:4])=[O:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](NC(=O)CN)C(=O)O
Agent: O=C([O-])CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Solvent: CCO
Solvent: O
Product: C[C@@H](NC(=O)CNC(=O)CSC(=O)c1ccccc1)C(=O)O
Temperature: 70 °C
Yield: 31.6 %

Procedure:
Succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate is prepared according to the method described by R. F. Schneider et al, Journal of Nuclear Medicine 25 (2), 223-229 (1984). Glycyl-D-alanine in an amount of 250 mg is dissolved in 15 ml of water and the mixture is heated to 70° C. on a water bath. Meanwhile, 1 g of succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate is dissolved in 40 ml of ethanol and the mixture is heated to 70° C. on a water bath. The solution of glycyl-D-alanine in water is added at once to the said ethanolic solution while stirring magnetically. The mixture is then refluxed for 1 hour. After cooling, the solution is evaporated to dryness under reduced pressure. The solid residue is shaken five times with 15 ml of acetone which is each time filtered off. Benzoylmercaptoacetylglycyl-D-alanine is precipitated from the collected filtrates by the addition of diethylether. The precipiate is filtered off and dried in vacuo over phosphorous pentoxide. In this manner 174 mg (yield 31.6%) of benzoylmercaptoacetylglycyl-D-alanine are obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH:18]=1
Reactant: Brc1cccnc1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cccnc1
Yield: 22.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 150 mg, 0.698 mmol) was reacted with 3-bromo-pyridine (220 mg, 1.395 mmol), 1,4-dioxane (10 mL), copper iodide (13.29 mg, 0.0698 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.33 mg, 0.209 mmol) and potassium phosphate (369.9 mg, 1.745 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 45 mg of the product (22.05% yield).
Reaction SMILES: [K].[S:2]([CH2:6][NH:7][C:8](=[S:11])SC)([OH:5])(=[O:4])=[O:3].[N-:12]=[N+:13]=[N-:14].[Na+]>O>[S:2]([CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)([OH:5])(=[O:4])=[O:3]
Reactant: CSC(=S)NCS(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [K]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)Cn1nnnc1S

Procedure:
A mixture of 45.3 g (0.19 mol.) of methyl sulfomethyldithiocarbamate potassium salt and 16.9 g. (0.26 mol.) of sodium azide in 425 ml. of water was heated at 80° for 4.75 hours. The reaction mixture was passed through an Amberlite IR-120H ion exchange resin column and eluted with water until the pH of the eluant became 3.5. The eluant was extracted with ether and the aqueous solution was evaporated to dryness to give 1-sulfomethyltetrazole-5-thiol.
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=O)[O:12]C2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=2)[NH:40][N:39]=1.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl>[CH3:7][O:10][P:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:12])[O:47][C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[NH:40][N:39]=[C:38]2[C:30]1[NH:29][C:37]2[C:32]([CH:31]=1)=[CH:33][CH:34]=[CH:35][CH:36]=2
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
Phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 230 mg of phenyl-phosphonic acid bis-(4-nitrophenyl) ester in solution in 4 ml of dichloromethane to which is added a solution of 120 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol and 72 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 4 ml of dichloromethane. After stirring for 2 hours at ambient temperature, the medium is treated with 4 times 50 ml of a saturated sodium bicarbonate solution, and then with 2×50 ml of a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and then concentrated to dryness to obtain 200 mg of crude phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26](O)=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23](/[CH:24]=[CH:25]/[C:26]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:29][CH:30]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccc(C=CC(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 52.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.67 g (16.7 mmol) of 4-butoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.04 g (yield 53%) of Compound 104 as pale yellow needles.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[C@@H:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:32]([SH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:1][S:2][C:3]1[C:4]([NH:13][C:14](=[O:25])[CH:15]([S:38][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCCCCCS
Reactant: CCCCCCCC[C@H](Br)C(=O)Nc1c(SC)ccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(SC)ccc2ncccc12
Reaction time: 18 h
Yield: 60.3 %

Procedure:
(S)-N-(6-Methylthioquinolin-5-yl)-2-bromodecanoic amide (39 mg, 0.09 mmol) in 1 ml of dry THF was added slowly to a suspension containing cesium carbonate (67 mg, 0.20 mmol) and hexanethiol (13 mg, 0.11 mmol) in 2 ml of THF. After 18 hours, the reaction was quenched with 2 ml of 1N HCl and extracted with ethyl acetate (4×10 ml). The organic phase was purified by silica gel column chromatography (eluent: 100% CHCl3) to yield 25 mg (60% yield) of the desired product. 1H NMR (CDCl3) δ8.85 (1H, d, J=3 Hz), 8.62 (1H, s), 8.05 (1H, d, J=9 Hz), 8.00 (1H, d, J=9 Hz), 7.65 (1H, d, J=9 Hz), 7.40 (1H, dd, J=9, 9 Hz), 3.55 (1 H, t, J=8 Hz), 2.80 (2H, t, J=8 Hz), 2.50 (3H, s), 2.20-1.30 (22H, m), 0.91 (6H, t, J=Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=O)[CH3:14].C.Cl.[CH3:18][O:19][NH2:20].C([O-])(=O)C.[Na+]>O>[CH3:18][O:19][N:20]=[C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])[CH3:14]
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C(C)c1nc(-c2cccnc2)[nH]c1C
Temperature: 5 °C

Procedure:
A 4.0 g (0.002 mole) amount of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone was dissolved in 150 ml of boiling water. The solution was clarified by treatment with activated charcoal, then filtered. The filtrate was added to a mixture of 2.0 g (0.025 mole) of O-methylhydroxylamine hydrochloride, 2.0 g (0.025 mole) of sodium acetate and 10 ml of water. This mixture was stirred and heated on a steam bath for 16 hours. The hot solution was clarified with activated charcoal and filtered. A 150 ml volume of water was added to the filtrate which had developed a heavy precipitate. The mixture was stirred and heated to boiling and ethanol was added in small portions to effect solution. The hot solution was clarified with activated charcoal and filtered. The filtrate was cooled at 5° C. with formation of a precipitate. The solid was collected by filtration, washed with cold water and dried and gave 1.7 g of the desired product as a white solid, mp 203°-205° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCc1ccc(C)cc1)c1csc(N)n1
Yield: 38.7 %

Procedure:
Ethyl 4-chloro-2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 19.88 g.), thiourea (5.59 g.), sodium acetate (9.99 g.), water (45 ml.) and ethanol (45 ml.) were treated in a similar manner to that of Example P-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)-acetate (syn isomer, 8.25 g.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[N:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1.C1COCC1.O.[OH-].[Li+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[N:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)nicotinate (0.70 g, 1.84 mmol) in a mixed solvent of THF (6 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.39 mg, 9.2 mmol). The reaction mixture was stirred at RT for 16 h. The reaction was quenched with aqueous 2N HCl to pH 5. The precipitate formed was collected by filtration, washed with water, dried to provide 2-(4-(benzo[d]thiazol-2-ylamino)-phenoxy)nicotinic acid as off-white solid. MS (ESI, pos. ion) m/z: 364.0 (M+1). IC50 (uM) +.
Reaction SMILES: C(OC([C:11]1([NH2:25])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:12]1=[O:24])=O)C1C=CC=CC=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:25][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)[C:12]1=[O:24]
Reactant: N#Cc1ccc(N2CCC(N)(C(=O)OCc3ccccc3)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(N2CCC(N)C2=O)cc1
Reaction time: 0.67 h
Yield: 80 %

Procedure:
50 g (0.15 mol) of 3-benzyloxycarbonyl-amino-1-(4-cyano-phenyl)-2-oxo-pyrrolidine are suspended in 600 ml of methanol, and 14.1 ml of 36% hydrochloric acid are added. After the addition of 2.5 g of 5% palladium on activated carbon, hydrogen is passed through at 45° C. After 40 minutes, the mixture is cooled, the catalyst is filtered off and the filtrate is concentrated to dryness. Recrystallisation from methanol/isopropanol yields 28.5 g (80%) of 3-amino-1-(4-cyanophenyl)-2-oxo-pyrrolidine hydrochloride.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[CH:5]=[N:4][C:3]=1[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]([CH2:7][CH2:8][CH3:9])[CH:5]=[N:4][C:3]=2[C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)=[CH:21][C:20]=1[F:28]
Reactant: CCCn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: CCCn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-propyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H14ClFN4, 342. Found, 341, 343.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>O>[S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C1NCCSc2ccsc21
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: c1cc2c(s1)CNCCS2

Procedure:
(acb) 1.0 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5(2H)-one was heated under reflux for 5 hours together with 15 ml of pyridine and 1.35 g of phosphorus pentasulfide. After cooling the mixture was poured into 90 ml of water and the crystals were removed by filtration. After chromatography on silica gel, the product was recrystallized from ethyl acetate. There was obtained 3,4-dihydro-thieno-[2,3-f][1,4]thiazepine-5(2H-thione as yellow crystals of m.p. 138°-139°.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:21][C:22]1([CH2:28][C:29]([NH2:31])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>>[NH2:31][C:29](=[O:30])[CH2:28][C:22]1([NH:21][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])[CH2:23][S:24](=[O:26])(=[O:27])[CH2:25]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (16 mg, 21%); MS (ESI, m/z): 454.3 (M+H+).
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][C:7]2[N:11]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=1.Cl.Cl[C:26]1C=CC2N(C(CCl)=C(C3C=CC(Cl)=CC=3)N=2)C=1.C([Mg]Br)#CC>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([CH2:6][C:4]3[C:5]([CH3:26])=[N:1][NH:2][N:3]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:12]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Reactant: Clc1ccc(-c2nc3ccc(Cl)cn3c2Cc2cn[nH]n2)cc1
Agent: CC#C[Mg]Br
Agent: Cl
Product: Cc1n[nH]nc1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to the experimental described for compound 227 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and prop-1-ynylmagnesium bromide. m/e+ 359 for C17H14Cl2N5 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)CBr
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(O)ccc3c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC(=O)OC)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A mixture of 6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (306 mg, 0.792 mmol), prepare in step 5 of Example 2, methyl bromoacetate (75 μL, 0.792 mmol) and potassium carbonate (556 mg, 4.02 mmol) in 35 mL of DMF was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated and extracted three times with water. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give methyl ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (364 mg, 96%) as a yellow solid, mp 149-151° C. Elemental Analysis for C28H25NO5 Calc'd: C, 73.83; H, 5.53; N, 3.07. Found: C, 73.55; H, 5.72; N, 3.08.
Reaction SMILES: C(OC(C1C=NN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CC)[C@@H](O)[C@H]3O)=C(NC(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)N=2)C=1)=O)C.[C:50]1([CH:56]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH2:57][NH:58][C:59]2[N:67]=[C:66]([NH:68][NH2:69])[N:65]=[C:64]3[C:60]=2[N:61]=[CH:62][N:63]3[C@@H:70]2[CH2:74][C@H:73]([NH:75][C:76](=[O:79])[CH2:77][OH:78])[C@@H:72]([OH:80])[C@H:71]2[OH:81])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[N+:88]([CH:91]([CH:94]=O)[CH:92]=O)([O-:90])=[O:89].[Na]>>[C:82]1([CH:56]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:57][NH:58][C:59]2[N:67]=[C:66]([N:68]3[CH:94]=[C:91]([N+:88]([O-:90])=[O:89])[CH:92]=[N:69]3)[N:65]=[C:64]3[C:60]=2[N:61]=[CH:62][N:63]3[C@@H:70]2[CH2:74][C@H:73]([NH:75][C:76](=[O:79])[CH2:77][OH:78])[C@@H:72]([OH:80])[C@H:71]2[OH:81])[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: NNc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Agent: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [Na]
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 1-[6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (example 168, step 3), by reaction of N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-hydrazino-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP1) and sodium nitromalonaldehyde (prepared as described by Fanta P. E. Org. Syntheses, Coll. Vol. 4 (1963), pp 844-845).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:14]([C:16]([O:20]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:16]([NH2:14])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 50 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of amine (S)—N1,N1-dimethyl-3-phenylpropane-1,2-diamine (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM) to afford 23 mg of biphenyl amide 51. Yield 45%.