Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C@H:14]1[C:17](OC)=[O:18]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:17]([C@@H:14]1[CH2:15][CH2:16][N:13]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18]
Reactant: Nc1cnccn1
Reactant: COC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of pyrazin-2-amine (1.626 g, 17.10 mmol) in THF (40 mL) was added isopropylmagnesium chloride (8.44 mL, 16.88 mmol) at 0° C. under N2. The resulting slurry was stirred at RT for 30 min. A solution of (S)-1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (0.92 g, 4.27 mmol) in THF (5 ml) was added to the reaction slurry. The reaction mixture was stirred at RT for 4 h. and concentrated. The residue was dissolved in EtOAc and washed with 1N HCl, water, and brine. The organic layer was dried over Na2SO4 and filtered. The crude product (1.05 g, 88%) was used in the next step without purification. 1H NMR (400 MHz, MeOD) δ ppm 1.38 (s, 9H) 2.31 (br s, 1H) 2.53 (ddd, J=8.81, 6.17, 2.39 Hz, 1H) 3.89-4.00 (m, 2H) 4.81-4.86 (m, 1H) 8.30-8.37 (m, 2H) 9.41 (s, 1H); LC/MS [M+H]+: 279; Ret time (Method F): 2.27 min.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[O:13].[OH-].[K+:18]>CO>[O:13]=[C:12]([CH:14]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([O-:16])=[O:15].[K+:18]
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=Cc1ccccc1
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A solution of trans-cinnamaldehyde (26.43 g) and pyruvic acid (11.9 mL) in 10 mL of methanol was stirred and chilled to 0-5° C. in an ice bath. To the chilled solution was added 35 nL of potassium hydroxide (16.83 g in 50 mL of methanol) over a period of 20 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The solution changed from a yellow to a dark orange and the precipitate was formed. The reaction mixture was chilled in the refrigerator overnight and the solid was collected by filtration, washed with 50 mL of methanol three times, 50 mL of ether and then air dried to afford 29.3 g of the desired 2-oxo-6-phenyl-3,5-hexadienoate as a yellow solid (61.0%). 1H NMR (DMSO-d6/D2O, 300 MHz), δ(ppm) 7.48 (d, 2H), 7.28 (m, 4H), 7.12 (d, 2H), 6.27 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=3[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20]>>[Br:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=3[CH:7]([CH2:21][C:19]#[N:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=O)c3cccc(Br)c3ccc2c1
Reactant: CCOP(=O)(CC#N)OCC
Product: Cc1ccc2c(c1)C=Cc1c(Br)cccc1C2CC#N
Yield: 69 %

Procedure:
The same procedure as in Step A of Example 2 was repeated using 0.86 g of 1-bromo-8-methyl-5-oxo-5H-dibenzo[a,d]cycloheptene and 1.4 ml of diethyl (cyanomethyl)phosphonate to give 0.64 g (69%) of the product as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@H:26]4[C@@H:30]5[O:31]C(C)(C)[O:33][C@@H:29]5[C@@H:28]([O:36][CH2:37][CH2:38][OH:39])[CH2:27]4)[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:11][CH:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([CH:26]4[CH2:27][CH:28]([O:36][CH2:37][CH2:38][OH:39])[CH:29]([OH:33])[CH:30]4[OH:31])[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: Cl
Solvent: CO
Product: CCCSc1nc(NC2CC2c2ccc(F)c(F)c2)c2nnn(C3CC(OCCO)C(O)C3O)c2n1
Temperature: 15 °C
Reaction time: 3.5 h
Yield: 90 %

Procedure:
The 2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)ethanol solution from above was cooled to 15° C., a solution of concentrated aqueous hydrochloric acid (465 kg) in methanol (623 kg), also tempered to 15° C., was charged. The reaction was stirred at 15° C. until the conversion criterion was fulfilled (>97%) and the phases were allowed to separate. The methanol-water layer, containing the product, was added to sodium bicarbonate (404 kg) in water (749 kg), keeping the temperature below 22° C. When pH≧6 the aqueous layer was extracted with ethylacetate (756 kg) and the phases were separated. The water layer was again washed with ethylacetate (1080 kg) whereafter the aqueous layer was discharged. The ethylacetate layers were combined and washed once with water (490 kg). The water content in the remaining ethylacetate solution was decreased to ≦0.8% (w/w) by vacuum distillation at 50° C., followed by a clear filtration and the concentration was adjusted to 6.2 L/kg 2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol. The mixture was heated to 50° C. and then iso-octane was added (1152 kg) during 45 minutes. The slurry was cooled to 0° C. during 2.5 hours and then kept at this temperature for 3.5 hours. The product was isolated and washed with a cold (<5° C.) mixture of ethylacetate (722 kg) and iso-octane (828 kg). Finally, the isolated product was dried under vacuum to give the title compound as a white solid (203 kg, 90% calculated from 2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: COc1cc(Br)ccn1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Temperature: 120 °C
Yield: 10.7 %

Procedure:
A mixture of (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.027 mmol), 4-bromo-2-methoxypyridine (10 mg, 2 equiv), CuI (0.5 mg, 10% mol), Pd(PPh3)2Cl2 (1.9 mg, 10% mol), diethylamine (1 mL), dry DMF (1 mL) was degassed, refilled with nitrogen gas (3×). The mixture was then heated in the microwave for 45 min at 120° C. LC-MS found the reaction was complete. The mixture was filtered, concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((2-methoxypyridin-4-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.4 mg). LC-MS Method 1 tR=1.92 min, m/z 485 (M+1); 1H NMR (CD3OD) 7.41-7.27 (m, 7H), 6.97 (m, 4H), 5.55 (q, 1H), 3.92 (s, 3H), 3.04 (m, 1H), 2.49 (m, 2H), 2.21 (m, 1H), 2.14 (s, 2H), 1.53 (d, 3H), 1.28 (t, 1H), 1.26 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=1.Cl>CN(C=O)C>[N:14]1[CH:9]=[CH:10][C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][C:13]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc(N)nc(C(=O)OCC)n1
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccnc(C(=O)OCC)n1
Temperature: 60 °C

Procedure:
Next, To a stirred solution of tert-butyl nitrite (268 mg, 2.34 mmol.) in DMF (5 mL) at 60° C. is added a solution of diethyl 6-aminopyrimidine-2,4-dicarboxylate (280 mg, 1.17 mmol) in DMF (0.5 mL) dropwise and mixture is heated at 60° C. for 18 hours. The mixture is cooled to room temperature and poured into 1N HCl (10 mL). The mixture is extracted three times with ethyl acetate and the combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=4:1) to give diethyl pyrimidine-2,4-dicarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[N:6]1[C:17](=[O:18])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:19])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Yield: 83.6 %

Procedure:
A stirred mixture of 15.0 g (10.1 mole) of 2-ethoxy-4-nitroaniline and 13.4 g (0.09 mole) of phthalic anhydride in 100 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The reaction mixture was cooled then poured into 700 ml of water to produce a solid which was collected by filtration. The solid was dissolved in methylene chloride, and the resultant solution washed first with an aqueous 10% potassium carbonate solution followed by an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 23.5 g of 2-(2-ethoxy-4-nitrophenyl)-1H-isoindol-1,3-(2H)-dione as a solid (mp 204°-206° C.).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([NH2:35])=[O:34]>>[C:33]([CH:28]1[N:27]([CH2:2][C:3]2[NH:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][N:13]=3)=[N:6][CH:5]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:4]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:32][CH2:31][O:30][CH2:29]1)(=[O:34])[NH2:35]
Reactant: NC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(N)=O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 48.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.85 g, 6 mmol) was reacted with morpholine-3-carboxamide (0.78 g, 6 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.54 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: N12CCN(CC1)CC2.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>C(OCC)C>[Cl:14][C:15]1[C:16]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:26][CH2:27]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1cccnc1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncccc2Cl)CC1
Temperature: -50 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
To a solution of 1,4-diazabicyclo[2.2.2]octane (DABCO, 680 mg, 6.06 mmol) in diethyl ether (20 mL) at −78° C. was added n-butyllithium (2.5M in hexanes, 3.0 mL) and stirring continued for 20 minutes. To this mixture was added 3-chloropyridine (700 mg, 6.16 mmol) as a solution in diethyl ether (5 mL). After 30 minutes, tert-butyl 4-oxo-1-piperidinecarboxylate (1.3o g, 6.52 mmol) was added as a solution in diethyl ether (1 mL). The reaction mixture was stirred at −78° C. for 2.5 hours then warmed to −50° C. and quenched with water. The mixture was allowed to warm to room temperature overnight. The layers were separated and the organic phase dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (gradient elution with 20% to 99% ethyl acetate:hexanes) to provide the title compound (110 mg, 9% yield). 1H NMR (500 MHz, CDCl3) δ 1.38 (br d, 2H, J=13.7 Hz), 1.50 (s, 9H), 2.73 (ddd, 2H, J=13.1, 13.1, 5.3 Hz), 3.31 (br m, 2H), 4.09 (br m, 2H), 7.25 (m, 1H), 7.74 (dd, 1H, J=7.8, 1.3 Hz), 8.46 (dd, 1H, J=4.7, 1.6 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:20]1([CH3:45])[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH:33]=[C:32]([CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:31]=[CH:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:34]([C:32]1[N:31]=[CH:30][N:29]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([CH3:45])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH:33]=1)([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: CCOC(=O)C(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
13.7 g (42.0 mmol) of cesium carbonate and 3.24 g (11.56 mmol) of 4-(t-butyloxycarbonylamino)butyl bromide were added to a solution of 4.0 g (10.51 mmol) of diethyl 2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]malonate in 67 ml of DMF, and the mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (heptane/ethyl acetate 1:1) gave the title compound (4.21 g, 73%). LC/MS: Rt=2.08 min, [M+H]+=552, (method A).
Reaction SMILES: CO[C:3](=[O:34])[CH2:4][NH:5][C:6](=[O:33])[C@H:7]([CH3:32])[NH:8][C:9](=[O:31])[CH2:10][NH:11][C:12](=[O:30])[CH2:13][NH:14][C:15](=[O:29])[C@H:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O.[NH2:36][NH2:37]>CO>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([NH:36][NH2:37])=[O:34])=[O:33])[CH3:32])=[O:31])=[O:30])=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NN
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)NN

Procedure:
A solution of Boc-Leu-Gly-Gly-Ala-Gly-OMe (2.0 g, 4 mmole, described in Example 10) and hydrazine hydrate (4.12 ml, 80 mmole) in methanol (50 ml) is stirred at 0° C for 4 hr. The solution is concentrated to 4 ml and added to diethyl ether (200 ml). The precipitate is collected, dissolved in methanol (4 ml) and added to diethyl ether (200 ml). The precipitate is collected and dried to give the title compound; mp 174° - 176.5° C; [α]D24 = -12.0° (c = 1, dimethylformamide).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OC)OC)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:25]=[CH:24][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)glycinamide (61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) in toluene (450 mL) was stirred at 75° C. for 5 days. Each day an additional 3 g of toluenesulfonic acids was added. The resultant reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue dissolved in dichloromethane. The organic solution was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. To the residual solid was subjected to column chromatography on silica gel eluting with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane was removed by co-evaporation with toluene for 3 time for subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CCl)cc1
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A mixture of 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione (3 g), 4-chloromethyl-2'-cyanobiphenyl (4.76 g) and potassium carbonate (2.64 g) in DMF (50 ml) was stirred at room temperature for 3 hours and then at 60° C. for 2 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless crystals (5.9 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH:19]=[CH:18][N:17]=[N:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][CH2:20][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Reactant: OCCCn1ccnn1
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCCn1ccnn1
Yield: 76.2 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 15 (see note a) above), 4-chloro-6-cyano-7-hydroxyquinoline (300 mg, 1.46 mmol), (prepared as described for the starting material in Example 1), was reacted with 3-(1,2,3-triazol-1-yl)propan-1-ol (242 mg, 1.9 mmol) to give 4chloro-6-cyano-7-(3-(1,2,3-triazol-1-yl)propoxy)quinoline (349 mg, 86%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>CCO>[NH:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:13])=[C:7]([F:12])[CH:8]=2)[N:3]=1)[NH2:15]
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Reactant: NN
Solvent: CCO
Product: NNc1cnc2cc(F)c(F)cc2n1
Reaction time: 8 h

Procedure:
The foregoing methodology was followed starting with 2-chloro-6,7-difluoroquinoxaline. This compound (4.00 g, 19.9 mmol) was dissolved in 100 ml of absolute EtOH. Hydrazine (1.4 ml, 44 mmol) was added, and the mixture heated at reflux for 21/2 hours. The mixture was cooled and allowed to stand overnight before collecting the resulting precipitate, yielding 3.80 g of an orange, solid 2-hydrazino-6,7-difluoroquinoxaline. This product (3.8 g, 19.4 mmol) was stirred in 30 ml triethylorthoformate and heated at reflux (100° C.) for 5 hours. The resulting product was cooled to room temperature, filtered and dried, yielding 2.63 g of 7,8-difluoro-1,2,4-triazolo[4,3-a]quinoxaline (13). The difluoro compound (13) (1.81 g 8.78 mmol) was added to glacial AcOH (25 ml) and treated with 80% monoperoxyphthalic acid Mg salt.6H2O (2.88 g, 4.66 mmol). The mixture was heated at 60°-70° C. overnight and initially went into solution, then a precipitate formed after 1-2 hours. This was allowed to cool, before pouring onto H2O. The precipitate was collected by filtration and air dried to yield 7,8-difluoro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (14).
Reaction SMILES: [OH:1]S(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]([OH:16])=[C:11](C(=O)C)[CH:12]=1>O1CCOCC1>[F:6][C:7]1[CH:12]=[C:11]([OH:1])[C:10]([OH:16])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1
Reactant: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(F)cc(O)c1O
Temperature: 28 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
H2SO4 (50 mL) was added to a solution of H3BO3 (89.3 g, 1.4 mol) in 1,4-Dioxane (300 mL) at 0° C. and stirred at 28° C. for 1 h. 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (50 g, 289 mmol) was added portion wise to the above solution over 1 h, maintaining the temperature at 0° C., after addition was complete, the reaction mixture was warmed to 25° C. and stirred for 16 h. Reaction mixture was quenched with cold water, solid separated was collected by filtration. The solid was suspended in diethyl ether (500 mL) and filtered to remove insoluble inorganic mass, ether layer was washed with cold water (2 to 3 times) followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude sticky solid. The crude solid was triturated over n-Hexane and filtered to afford 5-fluoro-3-nitrobenzene-1,2-diol (Int-25) (36 g, 86% yield) as pale yellow solid. MS (ESI): m/z 171.9 (M−1).
Reaction SMILES: Cl[Si](C)(C)C.[CH3:6][O:7][C:8](=[O:14])[CH:9]=[C:10]1[CH2:13][O:12][CH2:11]1.[CH3:15][Mg]Cl>C1COCC1.[Cu]I>[CH3:6][O:7][C:8](=[O:14])[CH2:9][C:10]1([CH3:15])[CH2:13][O:12][CH2:11]1
Reactant: C[Mg]Cl
Reactant: COC(=O)C=C1COC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COC(=O)CC1(C)COC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chlorotrimethylsilane (74 μl, 0.58 mmol) was solved in 1.5 ml THF. Copper(I) iodide (7 mg, 0.04 mmol) and oxetan-3-ylidene-acetic acid methyl ester (50 mg, 0.39 mmol) in 0.5 ml THF were added at room temperature and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was cooled to −15° C. and 3N methylmagnesiumchloride-solution (0.52 ml, 1.56 mmol) was added drop wise. The reaction mixture was stirred for 1 hour at room temperature, quenched then with saturated NH4Cl-solution and extracted with dichloromethane. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated to give 65 mg (92%) light yellow oil. The crude product was used for the next step without further purification.