Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[N:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.NC1CC2CCN1CC2>C(Cl)Cl.CO>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[C@@H:23]([NH:22][C:13]([C:11]1[S:12][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][N:10]=1)=[O:15])[CH2:24]2
Reactant: O=C(O)c1nnc(Sc2ccccc2)s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: NC1CC2CCN1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1nnc(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid (3.76 mmol) is placed in a flask and put under nitrogen. The acid is chilled in an ice bath. Oxalyl chloride (9 mL) that has also been cooled in an ice bath is added drop wise to the acid. The excess oxalyl chloride is removed under reduced pressure. The acid chloride is dissolved in about 5 mL CH2Cl2. The freebase of (R)-3-aminoquinuclidine (0.5 g, 2.52 mmol, 0.67 eq) is also dissolved in CH2Cl2 (5 mL), and the solution containing the acid chloride is cannulated into the flask containing the aminoquinuclidine. The reaction is stirred overnight at room temperature. The reaction mixture is diluted with MeOH, and poured through a Dowex 50AGWX2 CH+ column. The impurities are removed by washing the column with MeOH, and the product is eluted by washing the column with a solution containing 5% TEA in MeOH. The solvent is removed under reduced pressure, and the product is further purified by silica gel chromatography using a Biotage Flash 40M column (5% MeOH/CH2Cl2). This gives Example 64 (0.289 g, 22%) as a tan oil. MS (ESI) for C16H18N4OS2 m/z 347.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].I[CH2:12][CH2:13][O:14][CH:15]([O:17][CH2:18][CH2:19]I)[CH3:16]>O1CCCC1>[C:3]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH2:13][O:14][CH:15]([O:17][CH2:18][CH2:19][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:3]#[N:4])[CH3:16])#[N:4]
Reactant: CC(OCCI)OCCI
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCOC(C)OCCC(C#N)C(=O)OCC
Yield: 55.9 %

Procedure:
5.28 g (0.11 mol) of sodium hydride was added to 50 ml of dry tetrahydrofuran, and to this solution was added dropwise a mixed solution of 12.2 g (0.11 mol) of ethyl cyanoacetate and 10.0 g (0.027 mol) of bis(2-iodoethoxy)ethane, followed by 2-hours reflux under heating. After the reaction, the most portion of tetrahydrofuran was distilled off and the residue was added with 10 ml of water, neutralized with 1N hydrochloric acid and extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the resultant oily product was passed through a basic alumina (activity II)-packed column and eluted with petroleum ether-ether (1:4) to obtain 5.14 g of bis(3-cyano-3-carboethoxypropoxy)ethane, ##STR32## (yield: 56%). The property analyses of this compound gave the following results.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[N:13]=[C:12]2[S:14][C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])=[N:16][C:11]2=[CH:10][CH:9]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:20]1([C:18]([NH:17][C:15]2[S:14][C:12]3[C:11]([N:16]=2)=[CH:10][CH:9]=[C:8]([O:7][C:6]2[CH:23]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=4)[CH:3]=[CH:4][C:5]=2[O:24][CH3:25])[N:13]=3)=[O:19])[CH2:21][CH2:22]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
To a solution of N-[5-(5-amino-2-methoxyphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (93.0 mg, 261 μmol) in pyridine (2 mL) were added a solution of 3-(trifluoromethyl)benzoyl chloride prepared above in pyridine (3 mL) and N,N-dimethylpyridine-4-amine (28.9 mg, 237 μmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with 0.1N hydrochloric acid (30 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL), and dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20) to give the title compound (79 mg, 58%) as a white powder.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Clc1cccc(-c2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3cccc(-c4ccccc4)n3)CC2)cc1
Yield: 22.7 %

Procedure:
A mixture of 12.77 g (37.5 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 7.13 g (37.6 mmol) of 2-chloro-6-phenylpyridine, 8 g (58 mmol) of K2CO3 and 145 ml of absolute DMF were refluxed for 24 hours with stirring. The DMF was then removed by distillation in vacuo. CH2Cl2 /water was added to the residue, the mixture was shaken thoroughly, the phases were separated, and the aqueous solution was extracted repeatedly with CH2Cl2. After drying and filtering, the combined CH2Cl2 extracts were evaporated. The residue was taken up in ethyl acetate, whereupon a crystalline precipitate was produced, which was filtered off under suction. This solid (4.89 g) was a byproduct, to be precise 1-(4-hydroxyphenyl)-4-formylpiperazine. The ethyl acetate solution (filtrate) was evaporated, and the residue remaining (12 g) was chromatographed on a silica gel/CH2Cl2 /petroleum ether 1:2 column (diameter 2.2 cm, height 44 cm). Elution was effected using CH2Cl2 /petroleum ether 1:2, 1:1 and 2:1 mixtures, with CH2Cl2, and with CH2Cl2 /C2H5OH mixtures (0.5-2.0% by volume of C2H5OH). After preliminary fractions, 2.82 g (=22.7% yield) of 1-(4-hydroxyphenyl)-4-(6-phenylpyrid-2-yl)piperazine were obtained as a highly viscous oil;
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]([CH3:16])C(O)=O)=O.[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCCC1.[C:35]([OH:38])(=[O:37])C>C(O)C>[Cl:17][C:18]1[C:19]([CH3:28])=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:16][C:35]([OH:38])=[O:37]
Reactant: CC(=O)O
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: CC(C(=O)O)c1c(C=O)[nH]c2c1CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(Cl)ccc2c1C(=Cc1[nH]c3c(c1CCC(=O)O)CCCC3)C(=O)N2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of (2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 4.0 g of 5-chloro-4-methyl-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Addition of acetic acid (8 mL) resulted in the formation of a precipitate. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed with 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.8 g (80%) of 3-[2-(5-Chloro-4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.CC(O)=O.[NH2:31][NH2:32]>CCO>[CH3:2][C:1]1[C:4]2=[C:12]([CH3:13])[N:22]([C:21]3[CH:23]=[CH:24][C:18]([O:17][C:16]([F:25])([F:26])[F:15])=[CH:19][CH:20]=3)[C:9]([CH3:10])=[C:5]2[C:6]([CH3:7])=[N:32][N:31]=1
Reactant: NN
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nnc(C)c2c(C)n(-c3ccc(OC(F)(F)F)cc3)c(C)c12
Temperature: 0 °C

Procedure:
A solution of 1,1,2,2-tetraacetylethane (250 mg, 1.26 mmol) and 4-trifluoromethoxy aniline (170 μL, 1.26 mmol) was refluxed in EtOH (5 mL)/AcOH (1%) for 48 h. Hydrazine (100 μL, 3.15 mmol) was added and the mixture was refluxed for 1 h. The reaction mixture was poured into ice water (50 mL). The resulting precipitate was filtered and dried under vacuum to afford 1,4,5,7-tetramethyl-6-[4-(trifluoromethoxy)phenyl]-6H-pyrrolo[3,4-d]pyridazine as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.42 (d, 2H), 7.25 (d, 2H), 2.81 (s, 6H), 2.41 (s, 6H); MS (ESI) 336 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)[NH2:9])=[CH:4][CH:3]=1.Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:15]2)[NH:9][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:6][CH:7]=1
Reactant: NC(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2)CC1
Reactant: Clc1ncccn1
Solvent: C1CCOC1
Product: Fc1ccc(C(Nc2ncccn2)C2CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
α-(4-Fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanamine and 2-chloropyrimidine (equimolar quantities) are heated together in tetrahydrofuran at reflux temperature until the reaction is judged complete. The reaction mixture is concentrated and the residual material is partitioned between 1N NaOH solution and methylene chloride. The methylene chloride layer is dried and concentrated to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[CH:16]=[C:11]2[C:10](C=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:26][CH2:27][CH3:28])=[O:25].[C:49]1(C)C=CC=CC=1>>[CH2:27]([O:26][C:24](=[O:25])[CH:29]=[CH:49][C:10]1[C:11]2[C:12](=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[CH:16]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1)[CH3:28]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(-n3cncn3)ncc21
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cncn3)cc12
Yield: 96 %

Procedure:
A solution of 1-tert-butyloxycarbonyl-3-formyl-5-(1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine (1.5 g, 4.8 mmol) and (carboethoxymethylene)triphenylphosphorane (2.0 g, 5.8 mmol) in toluene (30 mL) was heated at 80° C. under nitrogen for 90 min. The mixture was allowed to cool and the solvent was evaporated in vacuo. The residue was chromatographed on silica eluting with 20% EtOAc in DCM to give a colourless solid. This was triturated with ether and the solid rechromatographed on silica with 20% EtOAc in DCM to give the title compound (1.77 g, 96%) as a colourless solid. mp 178°-181° C. 1H NMR (360 MHz, CDCl3) δ 1.37 (3H, t, J=7.1Hz), 1.73 (9H, s), 4.31 (2H, q, J=7.1Hz), 6.59 (1H, d, J=16.2Hz), 7.81 (1H, d, J=16.2Hz), 8.03 (1H, s), 8.14 (1H, s), 8.30 (1H, s), 9.21 (1H, s) and 9.26 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([NH2:10])=[O:9])[S:5][CH:6]=1.[CH2:11]([O:18][C:19](=[CH:22]N(C)C)[CH:20]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl>O.CN(C=O)C.CO>[CH2:11]([O:18][C:19]1[CH:22]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[C:8](=[O:9])[NH:10][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Reactant: Cc1csc(CC(N)=O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(-c2cc(OCc3ccccc3)c[nH]c2=O)n1
Yield: 73.1 %

Procedure:
2-(4-Methylthiazol-2-yl)acetamide (0.016 mol), 2-benzyloxy-3-(N,N-dimethylamino)propenal (0.017 mol), sodium hydride (0.032 mol), methanol (1.3 ml) and DMF (100 ml) were heated at 70° C. for 4 h. The reaction was cooled, acidified with 5.0N HCl(aq), and poured into water. The resulting precipitate was collected by filtration and dried to give the product as a brown solid (11.7 mmol, 73%). δH (360 MHz; CDCl3) 9.38 (1H, s), 7.47-7.34 (7H, m), 7.09 (1H, s), 5.21 (2H, s), 2.69 (3H, s).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH:13]=O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].Cl.[CH3:18][NH:19][CH3:20].C([BH3-])#N.[Na+].CO.C(Cl)Cl>CO>[CH3:18][N:19]([CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15])[CH3:20]
Reactant: CNC
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C=O)O[C@@H]2S1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde (40.00 mg; 0.16 mmol; 1.00 eq.) in MeOH (1.00 ml) was added dimethylamine hydrochloride (15.89 mg; 0.19 mmol; 1.20 eq.), and sodium cyanoborohydride (5.10 mg; 0.08 mmol; 0.50 eq.) in 0.5 mL MeOH. The reaction was stirred at room temperature for 15 min. The desired product was isolated by flash chromatography (KPNH column, 0 to 100% MeOH/DCM, 15CV) to afford (3aR,5R,6S,7R,7aR)-5-[(dimethylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (9.6 mg, 21%) as a white solid (once lyophilized).
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.[NH:32]1CCC[C@H:33]1C(O)=O.[Cu]C#N.O>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:29]1[CH:28]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])[C:4]([Cl:31])=[CH:3][C:2]=1[C:33]#[N:32]
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 120 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
To a suspension of 0.20 g (0.43 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 0.2 mL N,N-dimethylformamide was added 0.044 g (0.38 mmol) L-proline (commercially available, CAS RN 147-85-3) followed by the addition of 0.068 g (0.76 mmol) copper(I) cyanide. The resulting dark brown suspension was stirred at 120° C. for 17 hours. Then another 0.2 mL N,N-dimethylformamide were added and stirring was continued for another 7 hours at 120° C. The reaction was allowed to cool to room temperature, stirred for another 64 hours and then partioned between water and ethyl acetate. The resulting turbid mixture was filtered and washed with ethyl acetate. The layers of the filtrate were separated and the water layer extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The remaining light brown oil was dissolved in dichloromethane, treated with silica gel and then evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to afford 0.045 g (25%) of the title compound as a brown solid. MS (ESI): m/z=465.1 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.CC(C)=O>O>[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16]([O-:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.[Na+:2]
Reactant: O=C(O)c1cn2c(cnc3ccccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])c1cn2c(cnc3ccccc32)n1

Procedure:
Aqueous 2 N sodium hydroxide solution was added dropwise to a stirred suspension of 2 g of imidazo-[1,2-a]-quinoxaline-2-carboxylic acid in 20 ml of water until dissolution occured at a pH of 9-10. Acetone was added to the mixture to cause precipitation and the mixture was filtered to obtain 1.8 g of sodium imidazo-[1,2-a]-quinoxaline-2-carboxylate melting at >300° C.
Reaction SMILES: F[B-](F)(F)F.NC1O[C:9]([CH:20]([CH3:22])[CH3:21])=[N+:10]2[N:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=12.[C:23]1([C:29]#[C:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN1CCN(C)C1=O>[CH:20]([C:9]1[N:10]2[N:19]=[CH:18][C:17]3[C:12]([C:11]2=[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:22])[CH3:21]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CC(C)c1oc(N)c2c3ccccc3cn[n+]12
Agent: F[B-](F)(F)F
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 40 °C
Yield: 40.1 %

Procedure:
A mixture of 1-amino-3-isopropyloxazolo[4,3-a]phthalazinium tetrafluoroborate (1.58 g) and ethyl phenylpropiolate (1.74 g) in 1,3-dimethyl-imidazolin-2-one (30 ml) was maintained at 40° C. for 19 hours and then the resulting brown solution was poured into water (200 ml), and the mixture was extracted with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (1:1 v/v; 3×200 ml). The extracts were combined, dried over magnesium sulphate, and evaporated, and the resulting residue was subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (19:1 v/v), to give ethyl 3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazine-2-carboxylate (0.72 g) in the form of a yellow solid, m.p. 141°-142° C. [Elemental analysis: C, 77.1; H, 6.24; N, 7.8%; calculated C, 77.1; H, 6.19; N, 7.8%; NMR (in CDCl3) : 0.93 (3H, t, J=7 Hz), 1.57 (6H, d, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.35 (1H, septet, J=7 Hz), 7.23-7.50 (8H, m), 7.60-7.66 (1H, m), 8.35 (1H, s); Mass spectrum (electron impact) m/z=358].
Reaction SMILES: [Cl:1][CH2:2][C:3](=[CH2:40])[CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[CH2:40])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)[N:13]=2)=[CH:38][CH:39]=1
Reactant: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 4-((4-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (1.3 g) in DCM (8 mL) was added TFA (3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give 4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (1.1 g).
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].C(N(CC)CC)C.[NH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH2:16].Br.Br[CH2:26][C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=O>C(O)C>[CH3:3][C:2]1[N:16]([NH:15][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:26]=[C:27]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:7]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(C)=N
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccnc2)cn1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a mixture of ethyl acetimidate hydrochloride (2.0 g, 16.20 mmol) and triethylamine (3.28 g, 32.4 mmol) in ethanol (40 mL) was added a solution of tert-butyl hydrazinecarboxylate (2.14 g, 16.20 mmol) in ethanol (10 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. Then to the mixture was added a solution of 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (5.0 g, 17.9 mmol) and triethylamine (4.9 g, 48.6 mmol) in ethanol (20 mL). The reaction mixture was stirred at room temperature for 5 hours then heated to reflux overnight. The solvent was removed under reduced pressure and the residue was purified via silica gel chromatography (dichloromethane: methanol, 10:1) to give the title compound as an orange oil (0.76 g, 17.3%): 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.45 (d, 1H, J=6.3 Hz), 8.43 (s, 1H), 8.05 (d, 1H, J=6.3 Hz), 7.33-7.25 (m, 2H), 2.37 (s, 3H), 1.51 (s, 9H); ESIMS m/z 275 [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[C:25]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)[CH:24]=[CH:23][N:22]=2)[N:11]=[CH:10]1.Cl[CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[CH3:37][C:36]([CH3:39])([CH3:38])[C:35]([O:34][CH2:33][N:29]1[N:30]=[N:31][C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:26]=2)=[N:28]1)=[O:40]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Fc1ccc(-c2c(-c3cc(-c4nn[nH]n4)ccn3)ncn2Cc2ccccc2Cl)cc1
Product: CC(C)(C)C(=O)OCn1nnc(-c2ccnc(-c3ncn(Cc4ccccc4Cl)c3-c3ccc(F)cc3)c2)n1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield from 2-[1-[(2-chlorophenyl)methyl]-5-(4-fluorophenyl)imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 137) and 2,2-dimethyl-propionic acid chloromethyl ester according to the procedure for the preparation of Example 138. 1H NMR (300 MHz, CD3OD): δ 1.22 (9H, s), 5.30 (2H, s), 6.61 (2H, s), 6.61-6.62 (1H, m), 6.86-6.88 (2H, m), 7.09-7.39 (5H, m), 7.88 (1H, d, J=6.6 Hz), 7.96 (1H, s), 8.29 (1H, s), 8.55 (1H, d, J=5.1 Hz). [M+H] Calc'd for C28H25ClFN7O2, 546. Found, 546.