Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)=[O:4].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]([C:5]3[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]4[NH:15][N:14]=[N:13][N:12]=4)=[CH:7][CH:6]=3)=[O:4])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(CCl)c1ccc(OCc2nnn[nH]2)cc1
Solvent: CC#N
Product: O=C(CN1CCN(c2ccncc2)CC1)c1ccc(OCc2nnn[nH]2)cc1
Reaction time: 8 h

Procedure:
A mixture of 5-(4-chloroacetylphenoxymethyl)tetrazole (166 mg) and 1-(4-pyridyl)piperazine (214 mg) in acetonitrile (10 ml) was stirred overnight. The precipitate was collected, washed with acetonitrile and dried. A solution of this material in a small volume of 50% v/v acetic acid/water was transfered to a 1 inch preparative reverse phase hplc column (DYNAMAX (Trade Mark) C18 83-221-C) and eluted with water/acetonitrile/ trifluoroacetic acid in a gradient from 98:2:0.1 v/v/v to 60:40:0.1 v/v/v. The pure fractions, on freeze-drying, gave the title compound, 8.1 mg, as a white powder: NMR (D2O) δ8.39 (2H,d), 8.18(2H,d), 7.40(4H,m), 5.84(2H,s), 5.20(2H,s), 4.31(4H,bt), 3.87(4H,bt); m/e 380 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[C:7]([CH:13]=O)[N:6]=1.[NH2:20][NH2:21].CC[OH:24]>>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]2[C:9](=[O:24])[NH:20][N:21]=[CH:13][C:7]=2[N:6]=1
Reactant: N#Cc1ccc(Oc2ccc(F)cc2F)nc1C=O
Reactant: CCO
Reactant: NN
Product: O=c1[nH]ncc2nc(Oc3ccc(F)cc3F)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-2-formylnicotinonitrile (2.24 g, 8.6 mmol) in 15 mL of EtOH at 0° C. was added anhydrous hydrazine (1.4 mL, 43 mmol). The resulting mixture was stirred at RT for 5 min. The EtOH was removed under reduced pressure. The remaining residue was treated with AcOH (10 mL) and the reaction mixture was heated at 90° C. for 15 min, resulting in the precipitation of a yellow solid. The suspension was treated with ice and stirred for 5 min. The solid was filtered, rinsed with 5 mL of water followed by 2×2 mL of ether, and dried in a vacuum oven at 45° C. for 18 h to 2-(2,4-difluorophenoxy)pyrido[3,2-d]pyridazin-5(6H)-one as a yellow fluffy solid. MS (ESI, pos.ion) m/z: M+1=276.0
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35]([OH:37])=[O:36]>CN(C)C=O.O1CCCC1>[CH3:42][C:38]1[C:34]([C:35]([OH:37])=[O:36])=[C:33]([NH:32][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:41]=[CH:40][CH:39]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccc(N)c1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(C)c1C(=O)O
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
After a tetrahydrofuran solution (12.4 ml) of N-tert-butoxycarbonyl-L-methionine (1.24 g) was cooled to -15° C., N-methylmorpholine (0.55 ml) and isobutyl chloroformate (0.60 ml) were added to the solution, and the mixture was stirred for 20 minutes. Subsequently, an N,N-dimethylformamide solution (8.27 ml) containing 2-amino-6-methylbenzoic acid (0.50 g) and N-methylmorpholine (0.44 ml) was added dropwise, and the mixture was stirred at -15° C. for 0.5 hour and then at room temperature overnight. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 6-methyl-2-[(N-tert-butoxycarbonyl-L-methionyl)amino]benzoic acid (348 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[CH2:13]([O:15][C:16](=[O:32])[CH2:17][C@H:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][CH2:30]Br)=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:30][CH2:29][CH2:28][O:27][C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[C@H:18]([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:32])[CH2:19][CH2:20]3)=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1)#[N:7]
Reactant: CCCc1cc(C#N)ccc1O
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 40 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a mixture of 4-hydroxy-3-propylbenzonitrile (Example 29, 0.5 g, 3.1 mmol), ethyl [(1S-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 1.1 g, 3.1 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in DMF (10 mL) was added water (6 drops). The reaction mixture was stirred at 40° C. for 16 h and then concentrated under reduced pressure. The residue was taken up in water and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/Hexane (v/v) 1:20) gave 0.86 g (66%) of the title compound as a light yellow oil. LC-MS: RT=4.12 min; (M+H)+ 422.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:20])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: Cc1cc(=O)[nH]nc1-c1cccc([N+](=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1

Procedure:
A 22.7 g. portion of 5-methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone in 230 ml. of phosphorus oxychloride is heated on a steam bath for 3 hours. The reaction mixture is poured portionwise into crushed ice with stirring. The resulting solid is collected by filtration, washed with water and then dried yielding 5-methyl-6-(m-nitrophenyl)-3-chloropyridazine, m.p. 169°-171° C.
Reaction SMILES: C1C(CC2C=CC([N:14]=[C:15]=[O:16])=CC=2)=CC=C([N:17]=[C:18]=[O:19])C=1.C1C=C(CC2C=CC([N:33]=C=O)=CC=2)C(N=C=O)=CC=1.[CH2:39]([O:51]S(C1C=CC=CC=1)(=O)=O)[CH2:40]CCCCCCCCCC.[Na].FC(F)=C(F)F>O>[NH2:14][C:15]([O:51][CH2:39][CH3:40])=[O:16].[NH2:33][C:18]([NH2:17])=[O:19]
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Reactant: O=C=Nc1ccc(Cc2ccccc2N=C=O)cc1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: FC(F)=C(F)F
Agent: [Na]
Solvent: O
Product: CCOC(N)=O
Product: NC(N)=O

Procedure:
A urethane/urea prepolymer was prepared by reacting 70 percent by weight of a poly(propylene oxide) polyol VORANOL™ 2120 polyol (a trademark of The Dow Chemical Company) with 30 percent by weight of ISONATE™ 50 MDI (a trademark of The Dow Chemical Company; a 50:50 mixture of 4,4'-diisocyanatodiphenylmethane and 2,4'-diisocyanatodiphenylmethane). The following processes were carried out at 10° C. The prepolymer was fed continuously at a rate of 31.4 g/minute through a 1/2-inch (1.25 cm) stainless-steel tube fitted to one arm of a T. A 20-percent aqueous solution of a sodium dodecylbenzene sulfonate (RHODACAL™ DS-10, a trademark of Rhone Poulenc) was fed continuously at a rate of 4.7 g/minute through a 1/8-inch (0.31 cm) stainless-steel tubing fitted to the other arm of the T. The two streams were combined and passed through a static mixer to form a non-emulsified blend. The blend was then fed into a 1/2-inch (1.25 cm) stainless-steel tube fitted to one arm of a T attached to the input of a 70-mL centrifugal pump. Concurrently, water was pumped through a 1/8-inch (0.31 cm) tetrafluoroethylene tubing fitted to the other arm of the T, at the rate of 3.0 g/minute. The two streams were merged and mixed together under shear in the centrifugal pump operating at 650 rpm to form an HIPR emulsion.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:10]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:21].[Na+]>CC(C)=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][I:21])[C:10]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(N=Cc2ccccc2)C(=O)N1CCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CN(N=Cc2ccccc2)C(=O)N1CCCCI
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2,4 imidazolidinedione (prepared as described in Part I above) (43.1 g, 0.1467 mole), acetone (1200 ml) and sodium iodide (48.4 g, 0.3227 mole) is heated to reflux. Reflux is maintained for 5 hours. The mixture is filtered, collecting the insoluble. The filtrate is recharged with sodium iodide (10 g) and reflux is resumed and is maintained for 15 hours. After cooling to ambient temperature, the mixture is filtered, removing the insoluble NaCl (total recovery, 9.5 g, 110%). The filtrate is poured into H2O (2000 ml) while stirring. After stirring for 30 minutes, the solid is collected and air-dried to yield 51.5 g (0.1337 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2,4-imidazolidinedione.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([S:11][CH2:12]C(O)=O)=[C:5]([N+:16]([O-])=O)[CH:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C([O:29]C(C)C)(C)C.C(OCC)(=O)C>>[C:19]([N:16]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=2[S:11][C:12]1=[O:29])(=[O:21])[CH3:20]
Reactant: CC(C)OC(C)C
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(SCC(=O)O)c([N+](=O)[O-])cc1OC
Solvent: CCOC(C)=O
Product: COc1cc2sc(=O)n(C(C)=O)c2cc1OC
Yield: 34 %

Procedure:
Prepared analogous to Example 2(a) from [(4,5-dimethoxy-2-nitrophenyl)-thio]acetic acid and acetic acid anhydride with a yield of 34% of theory. M.p.: 164°-165° C. (diisopropyl ether/ethyl acetate).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:26]O>>[CH:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSC3CCCCC3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)C3CCCCC3)cc21

Procedure:
Prepared analogously to Example 2 from 6-(4-cyclohexylmercaptobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[C:11]2[C:6]=1[C:7](=[O:26])[C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:9]([CH3:19])[O:10]2)(=O)C.CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[OH:4][C:5]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:26])[C:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:9]([CH3:19])[O:10]2
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(=O)c(-c3ccccc3)c(C)oc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc2cc(O)cc(O)c2c(=O)c1-c1ccccc1
Yield: 78.8 %

Procedure:
10 g of 5,7-diacetoxy-2-methyl-isoflavone of m.p. 177°-178° C. prepared by the method described in Example 5 are boiled for 10 minutes with 50 ml of methanol and with a solution of 5 g of sodium hydroxide in 30 ml of water. On acidifying the solution with a 10% aqueous sulphuric acid, the precipitated product is filtered, affording 6 g of 5,7-dihydroxy-2-methyl-isoflavone, m.p. 228°-229° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].[CH3:23]I.O>C1COCC1>[CH3:23][O:1][CH2:2][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a solution of di-tert-butyl [(2S)-3-hydroxypropane-1,2-diyl]biscarbamate (2.45 g, 8.10 mmol) in THF (80 mL) at 0° C., was added NaH (60%, 357 mg, 8.91 mmol). The reaction was allowed to stir at 0° C. for 30 min, and then methyl iodide (0.556 mL, 8.91 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and then allowed to warm to rt and stirred for 3 h. Water was added and the reaction was extracted into EtOAc. The combined organic solutions were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography (SiO2, EtOAc/hexane) to yield the title compound as a white solid (895 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:23]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3
Reactant: NCCCc1cccnc1
Reactant: N#Cc1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1cn2c3c(c(NCCCc4cccnc4)c(F)c(N)c3c1=O)OCC21CC1
Yield: 25.1 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino-[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carbonitrile (150 mg, 0.52 mmol), 3-(pyridine-3-yl)propan-1-amine (176 mg, 1.3 mmol), and triethylamine (108 μL, 1.3 mmol) in DMSO (3 mL) was stirred at 120° C. for 15 hr. The reaction mixture was cooled and concentrated. The crude product was taken up in acetonitrile and purified by preparative HPLC to yield the title compound as a yellow solid (52.9 mg). MS (EP) m/z: 406.2 (M++1). (Calcd for C22H20FN5O2, 405.42). 1H NMR (400 MHz, D2O) δ 1.20 (2H, t), 1.50 (2H, t), 2.00 (2H, m,), 2.94 (2H, m,), 3.51 (2H, m), 4.14 (2H, s), 7.86 (1H, m), 8.03 (1H, m), 8.41 (1H, m), 8.52 (1H, m), 8.58 (1H, s)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:14]([CH3:15])=[CH:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C.[OH-].[Na+]>O>[CH3:15][C:14]1[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)=[N:11][N:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=1
Reactant: COc1ccc(Nc2nn(-c3ccccc3)cc2C)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cn(-c2ccccc2)nc1Nc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A 50 ml round bottom flask was charged with N-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazol-3-amine (0.37 g, 1.33 mmol), hydrobromic acid (2.16 ml, 39.74 mmol), and acetic acid (2.27 ml, 39.74 mmol). The reaction mixture was stirred at 110° C. for 4 h, then cooled to RT and diluted with water. The solution was neutralized with 6 N NaOH until a pH of about 6, upon which the product precipitated out of solution. The solid was filtered and dried under high vacuum to afford 4-(4-methyl-1-phenyl-1H-pyrazol-3-ylamino)phenol as a dark solid. MS m/z=266.1 [M+H]+. Calc'd for C16H15N3O: 265.31.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:29][S:30][CH3:31])[C:24]([F:28])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(=O)=O.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CC[C:42]#[N:43])=CC=1>>[F:28][C:24]1[C:23]([CH2:29][S:30][CH3:31])=[C:22]2[C:27]([C:19]([CH:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=3)[CH2:7][CH2:6][C:42]#[N:43])=[CH:20][NH:21]2)=[CH:26][CH:25]=1
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1c(F)ccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3)c[nH]c12
Product: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 2.20 g (4.62 mmol) of the compound from Example 67A in analogy to the synthesis of the compound from Example 50. 1.66 g (88% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:22][CH2:23][CH2:24][NH2:25])(C)(C)C.Cl>O1CCOCC1>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][CH2:23][CH2:24][NH2:25])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 125 °C

Procedure:
A mixture of 120 mg of 4-chloro-7-trifluoromethylquinoline and 250 mg of tert-butyl-N-(2-aminoethyl)carbamate was heated to 125° C. for two h. The mixture was cooled to room temperature and partitioned between 10% IPA/chloroform and saturated sodium bicarbonate. The aqueous layer was back extracted with 10% IPA/chloroform and the organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in EtOAc and washed with water, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The product was dissolved in MeOH (0.5 mL) and stirred with five equiv. of 4.0 M HCl in dioxane for 18 h. The reaction mixture was concentrated and the residue was recrystallized from MeOH to afford the title compound. MS (M+H)+=256.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CC1(C)C(C2C=NC(C)=C([N+]([O-])=O)C=2)=CCNC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: Cc1ncc(C2=CCNCC2(C)C)cc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95 %

Procedure:
To a solution of (5-bromopyridin-3-yl)acetic acid (1.00 g, 4.63 mmol) and morpholine (0.50 mL, 5.73 mmol) in DCM (50 mL) was added EDC (1.78 g, 9.30 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.26 mmol). The reaction mixture was allowed to stir at rt for 50 min and then diluted with DCM (50 mL) and 1N HCl (100 mL). The organic solution was separated and discarded. The aqueous solution was neutralized with sat. aq. NaHCO3 (100 mL) and was extracted with DCM (3×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol, 95%) as a light brown solid. LCMS (FA): Rt=1.11 min, m/z=287.0 (M+H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].[CH2:10]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[C:11]#[CH:12].[CH2:19]=O>O1CCOCC1>[C:1]([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:19][C:12]#[C:11][CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CCNC1
Reactant: C#CCN1CCCC1=O
Reactant: C=O
Solvent: C1COCCO1
Product: CC(=O)O[C@H]1CCN(CC#CCN2CCCC2=O)C1
Yield: 47.9 %

Procedure:
A mixture of 500 mg of (S)-3-acetoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 150 mg of paraformaldehyde and 50 mg of cupric chloride in 10 ml of dioxane was stirred at reflux under argon for 4 hours. The dioxane was evaporated, the residue was treated with 5 ml of 1N hydrochloric acid and extracted twice with ether. The aqueous acid was basified with 1 g of sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. This oil was purified by chromatography (alumina), giving 490 mg of the desired product as a yellow oil, [α]D26 =-3° (c, 1.02, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH3:17])[CH:9]=2)=[N:6][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH3:17])[CH:9]=3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCOc1cccc(-c2ncc(Br)cn2)c1
Product: CCCOc1cccc(-c2ncc(-c3ccc(OCc4ccccc4)cc3)cn2)c1

Procedure:
5-Bromo-2-(3-propoxyphenyl)pyrimidine and 4-benzyloxybenzeneboronic acid (preparation analogous to 3-benzyloxybenzeneboronic acid) are reacted analogously to Example 1 to give 5-(4-benzyloxyphenyl)-2-(3-propoxyphenyl)pyrimidine. ##STR41##
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[CH2:27]2)=[N:24][CH:25]=1>>[C:32]([N:31]([CH3:35])[CH:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=2)[CH2:27]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N(C)C1CCN(c2ccc(N)cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CC(=O)N(C)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide. LCMS calcd for C23H22F3N5O3 (m/e) 473, obsd 474 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Reactant: COc1ccc(I)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(C[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol, 1 eq.)), 4-iodoanisole (180 mg, 0.75 mmol, 1.5 eq.) in dioxane (4 ml) was added CuI(I) (20 mg, 0.05 mmol, 0.1 eq.), N,N-dimethylglycine (30 mg, 0.15 mmol, 0.3 eq.) and cesium carbonate (500 mg, 1.5 mmol, 3 eq.). The resulting mixture was stirred under Ar at reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure to give a residue, which was partitioned between water (10 ml) and ethyl acetate (10 ml). The ethyl acetate layer was separated and dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave a residue, which was passed through a plug of silica gel using dichloromethane (50 ml) as eluent to give 106 mg of desired product (51% yield).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.S(C)C.[O:12]=[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1>C(Cl)Cl>[O:12]=[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]1[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:8])=[CH:21][CH:20]=1
Reactant: O=c1ccccn1-c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CSC
Solvent: ClCCl
Product: O=c1ccccn1-c1ccc(CBr)cc1
Temperature: 0 °C

Procedure:
A solution of NBS (1.59 g, 8.94 mmol) and CH2Cl2 was cooled to 0°. To this solution (under Ar) was added Me2S (10.72 mmol, 0.78 mL) via syringe. This mixture was then cooled to -20° and added to a solution of the benzyl alcohol from Step 2 (1.2 g, 5.96 mmol) in CH2Cl2 via pipette. The reaction mixture was warmed to 0° and stirred for several hours. The residue was poured into ice water and extracted with CH2Cl2 (3×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound as a yellow solid, which will be used in the next step without further purification.