Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:3][C:4]([O:6][CH3:7])=O)C.[CH:8](OCC)=O.C[O-].[Na+].[NH2:16][C:17]([NH2:19])=[O:18]>C1(C)C=CC=CC=1.CCO>[CH3:7][O:6][C:4]1[C:3]([OH:1])=[N:16][C:17]([OH:18])=[N:19][CH:8]=1
Reactant: NC(N)=O
Reactant: CCOC=O
Reactant: COCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cnc(O)nc1O
Temperature: 110 °C
Reaction time: 8 h
Yield: 23.88 %

Procedure:
A mixture of methyl methoxylacetate (15 ml, 1.0 eq) and ethyl formate (12.18 ml, 1.0 eq) was added dropwise to slurry of sodium methoxide (8.17 g, 1.0 eq) in toluene (100 ml) at ice both. After dropping at room temperature and stirring overnight, the resulting solution was dried in vacuo. Then a mixture of residue, urea (9.09 g, 1.0 eq) and NaOMe (4.10 g, 0.5 eq) in EtOH (100 ml) was refluxed at 110° C. for 4 hrs. After the solvent was dried in vacuo, water and conc. HCl solution (5<pH<4) were added. After formation of white precipitate, the mixture was filtered and dried solid in vacuo. A product was obtained as a white solid (5.14 g, 23.88%)
Reaction SMILES: [CH2:1]([OH:4])CO.[OH-].[K+].CSC1[N:18]2[C:12]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH:16]=[CH:17]2)=[N:11][N:10]=1.Cl>O>[N:11]1[NH:10][C:1](=[O:4])[N:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][C:12]=12
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Reactant: OCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]nc2n1C=Cc1ccccc1C2
Reaction time: 2 h

Procedure:
To 2 ml of ethylene glycol was added 0.2 g of potassium hydroxide, followed by addition of 0.23 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine. The mixture was stirred at 150°-160° C. for 2 hours, after which water was added. The mixture was made acidic with 4N-hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and dried over Na2SO4. The solvent was evaporated off and the residue was treated with ethyl acetate. By the above procedure was obtained 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from methanol yielded light-brown needles melting at 207°-208° C. The following compounds were produced by procedures similar to that of the above Reference Example.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:7][CH:6]=1.[C:17]([CH2:19][C:20]([NH2:22])=[S:21])#[N:18].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(N(CCCC)CCCC)CCC>CO>[NH2:12][C:11]1[C:10]([C:13]#[N:14])=[C:9]([C:8]2[CH:15]=[CH:16][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[C:19]([C:17]#[N:18])=[C:20]([S:21][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:22]=1
Reactant: N#CCC(N)=S
Reactant: N#CC(C#N)=Cc1ccc(OCCO)cc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
428.4 g (2.0 mol) of 2-[4-(2-hydroxyethoxy)-benzylidene]malononitrile, 108.4 g (1.05 mol) of 2-cyanothioacetamide and 244.1 g (1.0 mol) of 4-chloromethyl-2-(4-chlorophenyl)-1,3-thiazole are suspended in 3.4 liters of methanol and 556.1 g (3.0 mol) of tributylamine are added over a period of 60 minutes. The mixture is subsequently stirred for 20 hours at room temperature and the product is filtered off. After drying in vacuo, the crude product (360.8 g, crude yield: 70% of theory) is suspended in 3 liters of dichloromethane and stirred for 2 hours at 35° C. The product is filtered off and dried in a high vacuum. The crystals, which are now white, can be purified further by recrystallization from tetrahydrofuran/water (1:1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=O)[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OCC)(=O)C>O1CCCC1>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:30])[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc2N(Cc2ccccc2)C(=O)C1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
μ-Chloro-μ-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminium (0.5M in toluene/15 ml, 7.5 mmol) was added to a solution of 1-benzyl-4-tert-butyloxycarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (2.95 g, 7.5 mmol) in tetrahydrofuran (23 ml) at -5° C. The resultant suspension was stirred at -5° C. for 15 minutes then allowed to warm to room temperature. Stirring was continued for a further 30 minutes followed by the addition of ethyl acetate (50 ml) and the mixture was washed with 0.2M sodium hydroxide solution (1.5 ml), and dried (MgSO4). The mixture was filtered through a pad of celite and evaporated to dryness. The crude product was purified by chromatography on silica gel with ethyl acetate-hexane (1:3) as eluant. (981 mg, 33%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OCC)=[O:11].[H-].[Na+].Cl>O1CCCC1>[O:11]=[CH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: CCOC=O
Reactant: N#CCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C=O)c1ccccc1
Temperature: 50 °C

Procedure:
3-Oxo-2-phenylpropanenitrile was prepared by addition of a mixture of phenylacetonitrile (0.90 g, 7.68 mmol) and ethyl formate (0.85 g, 11.5 mmol) dropwise to a stirred suspension of sodium hydride (0.41 g of 60%, 10 mmol) in tetrahydrofuran (4.5 mL). Reaction was rapid and exothermic. After heating in an oil bath at 50° C. for 20 min., the mixture was carefully acidified with dilute HCl and extracted with ethyl acetate. Extracts were washed with water, saturated NaCl solution, dried (MgSO4) and stripped to give 0.96 g (86%) of off-white solid, m. p. 148-153° C., Rf 0.5 (silica gel, ethanol:ethyl acetate:hexane=1:4:4).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][OH:11])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].Cl[C:15]1[C:23]2[C:22]3[CH:24]=[C:25]([C:28]#[N:29])[N:26]=[CH:27][C:21]=3[N:20](COCC[Si](C)(C)C)[C:19]=2[N:18]=[CH:17][CH:16]=1>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([C:3]1([CH2:10][O:11][C:15]2[C:23]3[C:22]4[CH:24]=[C:25]([C:28]#[N:29])[N:26]=[CH:27][C:21]=4[NH:20][C:19]=3[N:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)CCN(C)CC1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CCN(C)CC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4-ethyl-1-methylpiperidin-4-yl)methanol (223 mg, 1.4 mmol) in tetrahydrofuran (3.2 mL) was added sodium hydride as 60% dispersion in mineral oil (57 mg, 1.4 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (150 mg, 0.42 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 minutes, and then heated at 40° C. for 4 hours. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-10% methanol in methylene chloride) to afford the title compound as a white foam, which was used in the next step without any further purification (152 mg, 76%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([NH2:12])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc(Br)c(N)cc1O
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (12 g, 43.8 mmol) in MeOH (90 mL) was added Ni (2.4 g). The reaction mixture was stirred under H2 (1 atm) for 4 h. The mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether to give 2-tert-butyl-4-bromo-5-amino-phenol (C-27) (7.2 g, 70%). 1H NMR (DMSO-d6) δ 9.15 (s, 1 H), 6.91 (s, 1 H), 6.24 (s, 1 H), 4.90 (br s, 2 H), 1.22 (s, 9 H); ESI-MS 244.0 m/z (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42]N(C)C)=[O:39])=[CH:36][C:35]=1[O:48][CH3:49]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][CH2:6][N:7]([CH3:16])[CH3:8])=[O:39])=[CH:36][C:35]=4[O:48][CH3:49])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 66.5 %

Procedure:
A mixture of 0.0638 g (0.211 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0601 g (0.32 mmole) of toluenesulfonic acid monohydrate, 0.053 g (0.211 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 20 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) and then recrystallization from acetonitrile to give 0.0363 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-9) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][CH:3]=1.[BrH:9].N([O-])=O.[Na+].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].N#N>O.CC(C)=O>[Br:9][CH:15]([CH2:16][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:14]([O:18][CH3:19])=[O:17]
Reactant: Br
Reactant: Nc1ccc(F)cc1
Reactant: C=CC(=O)OC
Agent: N#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc(F)cc1
Temperature: -5 °C

Procedure:
A mixture of 4-fluoroaniline (27.75 g), acetone (500 ml) and hydrobromic acid (80 ml, 48%) stirred at -5° C. was treated over 30 minutes with a solution of sodium nitrite (21.0 g) in water (50 ml). Methyl acrylate (215 g) and cuprous bromide (0.04 g) were added. The internal temperature was allowed to rise in a carefully controlled manner; at 15° C. the evolution of N2 was vigorous. When the rate of N2 evolution decreased, the mixture was stirred at 25° C. for 1 hr to complete the reaction. The mixture was evaporated, and the residue was partitioned between water and toluene to give crude methyl 2-bromo-3-(4-fluorophenyl)propionate.
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C(OC(=O)C)(=O)C.N1C=C[CH:29]=[CH:28][CH:27]=1>>[C:27]([C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[NH:6][CH:16]=1)#[C:28][CH3:29]
Reactant: c1ccncc1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Solvent: CC(=O)OC(C)=O
Product: CC#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A dry 250 mL round-bottomed flask was charged with 5-iodouridine (10 g, 27 mmol Aldrich), anhydrous pyridine (30 mL) and acetic anhydride (30mL). The reaction was stirred at room temperature for 30 minutes under a nitrogen atmosphere and the solvent removed in vacuo. The compound was diluted with toluene (2 ×50 mL) and the toluene removed in vacuo. The product was purified on a 75 g flash chromatography column which was eluted with 90:10 (v:v) CHC13 :MeOH. The appropriate fractions were combined and concentrated to give the title compound as a white foam. This was used directly in the next stage.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH3:20])[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COc1ccccc1O
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1ccccc1OCCCOc1cccc(CC(OC)C(=O)O)c1

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-methoxyphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H24O6 [M+Na]+: 383.4.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].CO.[N:28]([Si](C)(C)C)=[N+:29]=[N-:30]>[Cu]I.CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:28]=[N:29][NH:30][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C#N)cn1)C[C@H](C)N2C(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 100 °C

Procedure:
A microwaveable vial was charged with 6-(((2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 9) (527 mg, 1.595 mmol), Copper (I) Iodide (30 mg, 0.158 mmol), methanol (0.333 ml), DMF (3 ml). Azidotrimethylsilane (0.423 ml, 3.19 mmol) was added to the solution, the vial sealed and heated at 100° C. for 1 h (microwave). Azidotrimethylsilane (0.211 ml, 1.59 mmol) was added to the vial and the mixture heated for a further 1 h (sealed vial, microwave). Azidotrimethylsilane (0.211 ml, 1.590 mmol), and copper (I) iodide (30 mg, 0.158 mmol) was added. The vial was resealed and heated for a further 1 h. The reaction solution was concentrated in vacuo, diluted with water (15 ml) and extracted with DCM (3×10 ml). The organics were combined and dried (hydrophobic frit). The mixture was concentrated and the sample purified by chromatography on a silica cartridge (50 g) eluting with a methanol/DCM gradient (0-10%). The appropriate fractions were combined and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (50 mg). LCMS (formate): Rt 0.71 min, MH+ 374
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[N:5]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)ncc1CO
Reactant: O=S(Cl)Cl
Product: COCc1nc(-c2ccc(OC(F)(F)F)cc2)ncc1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1N)=[O:5])[CH3:2].C(O)(=O)C.N(OC(C)(C)C)=O.[ClH:28]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1[Cl:28])=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(CCCOC)c1N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(CCCOC)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a mixture of 5-amino-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.22 g, 23.0 mmol) in dry acetonitrile (46 mL) was added anhydrous cuprous chloride (3.73 g, 37.7 mmol) and acetic acid (2.6 mL, 46.0 mmol). The mixture was cooled to 0° C. in an ice-water bath after which tert-butyl nitrite (4.9 mL, 36.8 mmol) was added over 10 minutes. The solution was allowed to warm to room temperature and stir for 4 h. To the solution was carefully added 6.0N hydrochloric acid (20 mL). The aqueous layer was extracted with methylene chloride (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the crude material. The product was purified by column chromatography on silica gel (eluting with ethyl acetate/hexanes, 1:1) to provide 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.71 g, 30%) as an orange oil. Mass spectrum: m/z: 247.3 (M+1).
Reaction SMILES: [C:1]([N:8]1[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][O:10][CH:9]1[C@H:17]([NH2:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].O>CO.O>[C:1]([N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][CH:9]1[C@H:17]([NH2:26])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COC(=O)C1=COC([C@H](N)CCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C(=O)O)=COC1[C@H](N)CCc1ccccc1

Procedure:
A solution of methyl N-Boc-2-[(1R)-1-amino-3-phenylpropyl]4-oxazolecarboxylate (388 mg) and potassium carbonate (1.5 g) in 90% methanol/water (10 mL) is brought to gentle reflux for 40 min. The reaction mixture is cooled, water is added and extracted thrice with ethyl acetate. The aqueous layer is acidified to pH 3 and extracted three times with ethyl acetate. The combined organic layer is washed twice with brine, dried (Na2SO4) and concentrated. The crude title product (372 mg) was >95% pure by NMR: 1H NMR (400 MHz, CDCl3) δ1.41 (s, 9H), 2.18 (m, 1H), 2.22 (m, 1H), 2.69 (m, 2H), 5.01 (m, 1H), 5.88 (bs, 1H, NH), 7.16 (m, 3H), 7.23 (m, 2H), and 8.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5](=[N:7][OH:8])[NH2:6].[N:13]1[CH:18]=[C:17]([C:19]([Cl:21])=[O:20])[CH:16]=[N:15][CH:14]=1.N1C=C(C(O)=O)C=NC=1.C(Cl)(=O)C(Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:19]([C:17]3[CH:18]=[N:13][CH:14]=[N:15][CH:16]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12].[N:13]1[CH:18]=[C:17]([C:19]([Cl:21])=[O:20])[CH:16]=[N:15][CH:14]=1
Reactant: NC(=NO)c1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1cncnc1
Agent: O=C(O)c1cncnc1
Product: Fc1ccc(-c2noc(-c3cncnc3)n2)cc1F

Procedure:
The titled compound was prepared according to the procedure of Method D using 3,4-difluoro-N′-hydroxybenzimidamide (Tyger) and pyrimidine-5-carbonyl chloride. The pyrimidine-5-carbonyl chloride was prepared by the reaction of pyrimidine-5-carboxylic acid (Maybridge, 138 mg, 1.0 mmol) with oxalyl chloride (Aldrich, 2 M, in CH2Cl2, 1.0 mL, 2.0 mmol) and a drop of dimethylformamide at room temperature over 1 hour with subsequent removal of volatiles under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (dt, J=10.5, 8.5 Hz, 1 H), 7.94-8.05 (m, 1 H), 8.11 (ddd, J=10.9, 7.7, 2.0 Hz, 1 H), 8.12 (none, 1H), 9.51 (s, 1 H), 9.54 (s, 2 H) ppm; MS (DCI/NH3) m/z 261 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>[OH-].[Na+].O1CCOCC1>[C:1]1([S:7]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
Benzenesulfonyl chloride (2.5 ml, 19 mmol) was added to a solution of 6-aminohexanoic acid (1 g, 7.62 mmol) in 2N NaOH (22 ml) and dioxane (3 ml), while stirring at 0° C.-5° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was washed with ethyl acetate (50 ml), then acidified to pH 2 with 37% hydrochloric acid and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was triturated with hexane. The solid was collected by filtration and dried under vacuum at 50° C. affording 1.1 g of the title compound (55% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:13]1[CH2:18][CH2:17][CH2:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:15]1([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:16][CH2:17][CH2:18][N:13]=[CH:14]1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: C1=NCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N2C=NCCC2)cc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a stirred solution of 2.0 g (11.76 mmol) of 5-fluoro-3-methyl-2-nitro-aniline in 10 mL of DMSO was added 1.2 g (14.11 mmol) of 1,4,5,6-tetrahydropyrimidine, and 2.43 g (17.64 mmol) of potassium carbonate, and the mixture was heated at 100° C. for 10 hrs, cooled, diluted with water, and extracted with Ethylacetate containing 5% methanol. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent furnished the residue, which was chromatographed (20% of 2M ammonia in methanol and dichloromethane) to produce 1.85 g (67%) of the product as red solid. 1H NMR (400 MHz, CD3OD) δ 7.89 (1H, s), 6.53 (1H, d, J=2.57 Hz), 6.44 ((1H, d, J=2.1 Hz), 7.04 (1H, d, J=2.1 Hz), 3.70 (2H, t, J=6.0 Hz), 3.41 (2H, t, J=5.65 Hz, 2.43 (3H, s), 2.05 (2H, m) LCMS (M+H)+ m/z 235 (t=0.78 min).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)[CH:19]([CH3:21])[CH3:20].CC#[N:27]>CN(C=O)C>[NH2:27][C:6]1[CH:5]=[CH:4][C:3]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:20][CH2:19][CH3:21])=[CH:12][CH:11]=2)=[CH:2][CH:7]=1
Reactant: CC#N
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccccc1N=Nc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1ccc(N=Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a solution of the aminoazobenzene (1 eq) and DIPEA (2 eq) in 1:1 MeCN:DMF at 0° C. was added 2-triethylammonium acetic acid chloride chloride8 (1.5 eq) in 1:1 MeCN:DMF and stirred for 15 min, then warmed to ambient temperature and stirred for 1-12 h at which time the solvent was removed in vacuo for purification by reverse phase silica gel chromatography (0.1% formic acid in H2O, gradient up to 50% MeCN: 0.1% formic acid in H2O).