Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:25][CH2:26][C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: c1cc(OC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentyloxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 24, Step 2) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[CH2:6]([Cl:12])[CH2:7][O:8]CCO.C(OC=C)=C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]([O:3][CH2:4][CH2:5][O:8][CH2:7][CH2:6][Cl:12])=[CH2:2]
Reactant: C=COCC
Reactant: OCCOCCCl
Agent: C=COC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=COCCOCCCl

Procedure:
315 ml (3.3 moles) of ethyl vinyl ether and 12.5 mmoles of mercuric acetate, which rapidly dissolves, are fed into a three-neck flask of 500 ml capacity provided with a reflux condenser and mechanical stirrer and maintained under a nitrogen stream. 0.660 moles of diethylene chlorohydrin are dripped into the solution, the mixture then being heated under reflux until the ratio (gas-chromatographic analysis) of the chlorohydrin to the corresponding vinyl ether remains constant (20 hours). The mixture is then treated with anhydrous potassium carbonate (20 grams), most of the excess ethyl vinyl ether and by-product ethyl alcohol are removed under vacuum and the remaining mixture is filtered through a Gooch crucible. The filtrate is diluted with chloroform and extracted with water, the organic phase being dried with anhydrous sodium sulphate and filtered. After evaporating the solvent, the crude product is purified by preparative HPLC (stationary phase silica gel).
Reaction SMILES: [OH:1]O.[C:3]([OH:10])(=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>O[W](O)(=O)=O.C(O)(C)(C)C>[OH:1][CH2:8][CH:7]1[O:10][C:3](=[O:9])[CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: C=CCCCC(=O)O
Agent: O=[W](=O)(O)O
Solvent: CC(C)(C)O
Product: O=C1CCCC(CO)O1
Temperature: 70 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A total of 2 ml of 30% by weight hydrogen peroxide aqueous solution was added dropwise to a stirred mixture of 1.12 g (10 mmol) of 5-hexenoic acid, 25 mg (0.1 mmol) of tungstic acid, and 15 ml of t-butyl alcohol at room temperature, followed by stirring at 70° C. for 8 hours. As a result, δ-hydroxymethyl-δ-valerolactone was produced in a yield of 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH2:24]([Mg]I)[CH3:25]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:12])[CH2:24][CH3:25])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CC[Mg]I
Reactant: CCCCCC(CC(=O)OC)c1cc(C=O)c(OC)cc1OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(CC(=O)OC)c1cc(C(=O)CC)c(OC)cc1OC
Reaction time: 0.67 h

Procedure:
A solution of 644 mg (2.0 mmol) of methyl 3-(2,4-dimethoxy-5-formylphenyl)octanoate [prepared as described in Preparation 32(ii)] in 10 ml of tetrahydrofuran was added dropwise over a period of 5 minutes to a solution of 1.2 ml (2.2 mmol) of a 1.8 M solution of ethylmagnesium iodide in diethyl ether diluted with 20 ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 40 minutes. The reaction was then terminated by the addition of a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with a mixture of ethyl acetate and hexane. The extract was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, giving the title compound as a crude product. This product was dissolved in 40 ml of methylene chloride, and 3.48 g of manganese dioxide were added to the resulting solution. The resulting mixture was stirred for 1 hour, after which a further 3.48 g of manganese dioxide were added. The mixture was then stirred for 12 hours, and then a further 1.72 g of manganese dioxide [8.68 g (99.8 mmol) in total] were added to the mixture, which was then stirred for 8 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was triturated with hexane to give approximately pure crystals of the title compound. The compound was firther purified by column chromatography through 10 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 5:1 to 3:1 by volume as the eluent, to give 416 mg (yield 59%) of the desired propionyl derivative, melting at 75.5-77.5° C. (from hexane).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH2:12](O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O>[C:1]1([C:7](=[CH2:12])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: CCO
Agent: C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Product: C=C(C#N)c1ccccc1

Procedure:
Phenylacetonitrile (117 g, 1.0 mol), 37% formaldehyde solution 85 g, 1.0 mole of formaldehyde), ethanol (100 ml), and 40% benzyltrimethylammonium hydroxide (Triton B) (2 ml) were mixed in a 500 ml 3-necked round-bottomed glass flask equipped with a magnetic stirrer, water-cooled condenser and thermometer. A static atmosphere of argon was maintained throughout the course of the reaction. The reaction mixture was mixed and heated to reflux temperature whereupon the heat of reaction was sufficient to maintain the reaction without external heating. After ten minutes the mixture had formed two layers. It was cooled and the top layer containing mostly alcohol and water was separated. The lower viscous yellow layer was dissolved in acetone and charged to a distillation flask together with 0.1 g hydroquinone. Distillation under reduced pressure yielded 30 g of a water-white distillate boiling at 95°-100°/1.0 mm Hg (23 percent of theory). 1H NMR: (CDCl3, TMS), δ7.0 (S, 5H), 6.1, 5.85 (s, s, 2 H).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([NH:44][C@H:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:46](=[O:47])[C@H:45]([NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH3:49])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(OC(=O)[C@@H](C)NC(=O)OC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 81 %

Procedure:
In analogy to Example 5, 300 mg (0.59 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (R)-2-tert-butoxycarbonylaminopropionic acid and, after workup and purification, 324 mg (81%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1[Cl:13].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19]>C(OCC)C>[F:16][C:17]([F:24])([F:23])[C:18]([C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([Cl:14])=[C:12]([Cl:13])[CH:7]=1)=[O:19]
Reactant: Clc1ccc(Br)c(Cl)c1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-BuLi (16.5 ml, 2.5M in hexane) is added over 20 minutes to a solution of 5-bromo-1,2,6-trichloro-benzene (10.2 g) in diethyl ether (150 ml) under nitrogen at −78° C. After 20 minutes at −78° C., a solution of ethyl trifluoroacetate (5.15 ml) in diethyl ether (50 ml) is added over 15 minutes to the reaction mixture. After 40 minutes at −78° C., the reaction mixture is slowly warmed up to room temperature and then quenched with a saturated aqueous solution of NH4Cl. The aqueous phase is extracted three times with diethyl ether. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified by vacuum distillation to yield 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (9.20 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])[CH:5]=[CH:6][CH:7]=1.[N:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:18]2=[C:17]([C:24](O)=[O:25])[CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH:14][C:24]([C:17]3[CH:16]=[N:15][N:19]4[CH:20]=[CH:21][CH:22]=[N:23][C:18]=34)=[O:25])=[C:10]([CH3:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: Cc1n[nH]c(-c2cccc(Cl)c2)c1N
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]nc(-c2cccc(Cl)c2)c1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 15 h
Yield: 45.1 %

Procedure:
A mixture of 5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine (113.3 mg, 0.546 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (109.5 mg, 0.6712 mmol), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (338.2 mg, 0.652 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and 4-dimethylaminopyridine (19.1 mg, 0.156 mmol) in 8.0 mL N,N-dimethylformamide was stirred at 50° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 86.9 mg (45%) of N-(3-(3-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=353.0; 1H NMR (400 MHz, DMSO-d6) δ: 12.90 (s, 1H), 9.37 (d, J=7.0, 1H), 9.30 (s, 1H), 8.86 (dd, J=4.1, 1.3, 1H), 8.69 (s, 1H), 7.80 (d, J=12.1, 1H), 7.72 (d, J=7.6, 1H), 7.37 (t, J=7.8, 1H), 7.32 (dd, J=6.9, 4.4, 2H), 2.18 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:24]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:28]2C=CC=CC=2N=N1.[NH2:44][C:45]1[CH:50]=[C:49]([O:51][C:52]2[CH:57]=[CH:56][C:55](CN)=[C:54]([N+:60]([O-:62])=[O:61])[CH:53]=2)[CH:48]=[CH:47][N:46]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:44][C:45]2[CH:50]=[C:49]([O:51][C:52]3[CH:57]=[CH:56][C:55]([NH:24][CH3:28])=[C:54]([N+:60]([O-:62])=[O:61])[CH:53]=3)[CH:48]=[CH:47][N:46]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCc1ccc(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNc1ccc(Oc2ccnc(NC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 1-(tert-butoxy)carbonylpiperidine-4-carboxylic acid (1 eq) in N,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP (2 eq) and the mixture was stirred at ambient temperature until homogeneous. To it was added [4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and the resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the resulting tert-butyl-4-(N-{4-[4-(methylamino)-3-nitrophenoxy]-2-pyridyl}carbamoyl)piperidinecarboxylate was purified by silica gel chromatography. MS: MH+=472.2.
Reaction SMILES: CC1(C)OI([C:11]([F:14])([F:13])[F:12])C2C1=CC=CC=2.[C:16]([O:19][C:20]1([CH2:33][CH:34]=[CH2:35])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)(=[O:18])[CH3:17]>[Cu]I.CO>[C:16]([O:19][C:20]1(/[CH:33]=[CH:34]/[CH2:35][C:11]([F:14])([F:13])[F:12])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]1)(=[O:18])[CH3:17]
Reactant: CC1(C)OI(C(F)(F)F)c2ccccc21
Reactant: C=CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]I
Solvent: CO
Product: CC(=O)OC1(/C=C/CC(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A flame-dried vial equipped with a magnetic stir bar was charged with Togni reagent (2.0 g, 7.0 mmol) and CuI (34 mg, 0.35 mmol), and was sealed with a septum. The vial was evacuated and backfilled with N2 for three times. MeOH (8 mL) and tert-butyl 4-acetoxy-4-allylpiperidine-1-carboxylate (4.5 g, 14 mmol) were then added via syringe. The vial was kept at 80° C. for 2 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by a standard method to afford the product (2.1 g). 1H NMR (400 MHz, CHLOROFORM-d) δ: 1.47 (s, 9H), 1.66-1.77 (m, 2H), 2.00-2.07 (m, 3H), 2.22 (d, J=13.43 Hz, 2H), 2.85 (qdd, J=10.61, 10.61, 10.61, 7.25, 1.21 Hz, 2H), 3.11 (t, J=11.82 Hz, 2H), 3.81 (br. s., 2H), 5.58 (dt, J=15.98, 7.19 Hz, 1H), 6.05 (d, J=16.12 Hz, 1H).
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=O)=[C:23]([F:29])[CH:22]=2)[N:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[C:15]=1[Cl:34].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:3])=[C:23]([F:29])[CH:22]=2)[N:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[C:15]=1[Cl:34]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: COC(=O)c1nc(-c2ccc(C=O)c(F)c2)c(F)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)cc1F
Temperature: 23 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
Dimethyl 1-diazo-2-oxopropylphosphonate (290 mg, 1.5 mmol, 1.2 equiv) was added to a stirred mixture of methyl 4-amino-3-chloro-5-fluoro-6-(3-fluoro-4-formylphenyl)picolinate (410 mg, 1.3 mmol, 1.0 equiv) and solid potassium carbonate (350 mg, 2.5 mmol, 2.0 equiv) in methanol (12 mL) at 23° C. The resulting cloudy pale yellow mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4×60 mL). The organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (33% ethyl acetate in hexanes) to afford the title compound as a white powder (150 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)nc1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 ). The mixture was stirred at room temperature for 3 h, recolled to 0° C., and saturated aqueous K2CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2% MeOH/CH2Cl2) gave 7.5 g (59%) of a yellow solid, mp 49°-51° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:24]2[CH:25]=[C:26]([C:30]3[O:35]C(C)(C)[O:33][C:32](=O)[CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:32](=[O:33])[CH2:31][C:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:25]=1)=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G48) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a light yellow solid (79 mg).
Reaction SMILES: C(N(CC)CC)C.Br.[NH2:9][CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[O:16]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][C:11]2=[O:12])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NC1CCOC1=O
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCCC1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Triethylamine (20.0 ml, 143.9 mmol) was added to a suspension of α-amino-γ-butyrolactone hydrobromide (7.28 g, 40.0 mmol) in dichloromethane (80 ml), and then 20 minutes were spent in adding dropwise a solution of 4-phenoxybenzenesulfonyl chloride (11.0 g, 40.9 mmol) in dichloromethane (40 ml) to the mixture with ice-cooling. After this mixture was stirred at room temperature for 2 hours, the solvent of the reaction mixture was evaporated under reduced pressure. The residue was acidified with water and hydrochloric acid (1N), and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to give the title compound (8.74 g, yield 73%) as a white powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10](Br)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[C-:29]#[N:30].[Na+].C[N:33]([CH3:36])C=O>>[C:29]([C:24]1[N:23]=[C:22]([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:36]#[N:33])[N:7]=3)[N:9]=2)[CH:27]=[CH:26][CH:25]=1)#[N:30]
Reactant: CN(C)C=O
Reactant: [C-]#N
Reactant: COc1ccc(C2=CC(Br)(c3ccccn3)NC(c3cccc(Br)n3)=C2)cc1
Agent: [Na+]
Product: COc1ccc(-c2cc(-c3cccc(C#N)n3)nc(-c3cccc(C#N)n3)c2)cc1

Procedure:
To a solution of 6,6'-dibromo-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine from example 6 (30.0 g, 0.06 mole) in anhydrous dimethyl formamide (Aldrich HPLC grade, 240 mL) in a 500 mL 3 neck round bottom flask equipped with a condenser, nitrogen inlet adapter, and a mechanical stirrer (glass rod with teflon blade) was added cuprous cyanide (Aldrich, 21.5 g, 0.24 mole) and sodium cyanide (Aldrich, 11.8 g, 0.24 mole) under efficient stirring and nitrogen flow. The mixture was heated on an oil-bath equipped with a temperature controller for about five hours at 155° to 160° C. The reaction mixture was then filtered at 150° C. to remove hazziness. The filtrate was evaporated to dryness under vacuum at 65° to 70° C. The residue was treated with water (30 mL) and stirred with sodium cyanide solution (20.00 g sodium cyanide into 80 mL of water) for about 3 to 4 hours at about 45° C. The crystalline mass of 6,6"-dicyano-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine was isolated by filtration, washed with water (250 mL), and then dried under vacuum for 16 hours at 50°-55° C. to yield 22.2 g of tan colored product (95 % of theory). The crude product was recrystallized from methylene chloride (1 g in 90 mL). TLC: (silica gel plate; ethyl acetate:hexane::1:1 v/v) showed a single spot (Rf=0.5 approx.). Infrared spectrum: nitrile band around 2200 cm-1 ; mass spectrum (FAB): M+H=390 m/e; 1H NMR (CDCl3): 3.9 (s, 3H, OCH3), 7.1 (d, 2H), 7.77 (d, 2H), 7.87 (d, 2H), 8.03 (t, 2H), 8.79 (s, 2H) and 8.85 ppm (d, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH:40]([CH3:42])[CH3:41])[NH2:38].CN1CCOCC1>CN(C=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:38][C@@H:37]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36]([O:35][CH3:34])=[O:43])=[O:12])=[O:6])[CH2:17][CH3:18]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](CC(C)C)C(=O)OC)c1
Reaction time: 1 h
Yield: 88 %

Procedure:
3-[(Dipropylamino)carbonyl]benzoic acid, (1.24 g, 5 mmol) is combined with EDC (0.95 g, 5 mmol) and HOBT (0.69, 5.1 mmol) in 10 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of L-leucine methyl ester hydrochloride (0.9 g, 5 mmol) and 0.55 mL (5 mmol) of 4-methylmorpholine in 5 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 50% ethyl acetate in heptane, affords 1.65 g (4.4 mmol, 88%) of the title compound as a colorless oil which crystallizes on standing. 1H NMR (CDCl3) δ 7.82 (m, 1H), 7.77 (s, 1H), 7.51-7.44 (m, 2H), 6.65 (d, J=8 Hz, 1H), 4.84 (m, 1H), 3.77 (s, 3H), 3.46 (br t, 2H), 3.14 (br t, 2H), 1.78-1.65 (m, 5H), 1.53 (m, 2H), 0.99 (m, 9H), 0.75 (br t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CONC>CN(C=O)C>[CH3:15][O:19][N:20]([CH3:21])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=1)=[O:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid (0.62 g, 2.8 mmol), HATU (1.3 g, 3.4 mmol) and di-isopropylethylamine (1.72 ml, 3.5 mmol) in DMF (20 ml) is stirred at room temperature for 5 minutes. N-Methoxy-N-methylamine hydrochloride (0.33 g, 3.4 mmol) is added and the reaction is stirred at room temperature for 2 hours. The solvent is concentrated in vacuo and the residue dissolved in EtOAc (30 ml), and washed with sat. aq. NaHCO3 (20 ml), 0.1N HCl (20 ml), dried (MgSO4) and concentrated in vacuo to yield a brown oil. Purification by flash chromatography (SiO2, 30% EtOAc in iso-hexane) yields 3-amino-6-bromo-pyrazine-2-carboxylic acid methoxy-methyl-amide as a yellow solid [M+H]+261.