Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:31]=[CH:30][C:6]2[O:7][CH2:8][O:9][C:10]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:11]=3[C:12](=CCCN3CCC[C@@H](C(O)=O)C3)[C:5]=2[CH:4]=1.ICI.CN(C)C=[O:38]>>[Cl:2][C:3]1[CH:31]=[CH:30][C:6]2[O:7][CH2:8][O:9][C:10]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:11]=3[C:12](=[O:38])[C:5]=2[CH:4]=1
Reactant: O=C(O)[C@@H]1CCCN(CCC=C2c3cc(Cl)ccc3OCOc3ccc(Cl)cc32)C1
Reactant: CN(C)C=O
Agent: Cl
Solvent: ICI
Product: O=C1c2cc(Cl)ccc2OCOc2ccc(Cl)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
(R)-1-(3-(2,10-Dichloro- 12H-dibenzo[d,g][1,3]-dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid hydrochloride ##STR7## 2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, prepared similarly as described in Journal of the American Chemical Society 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol) were dissolved in dry N,N-dimethylformamide (226 ml). Dried and powdered potassium carbonate (8.3 g) was added and the mixture was heated at 105° C. for 5 h and left overnight at room temperature. The reaction mixture was poured on ice (220 g). The precipitate was collected by filtration after 0.5 h and dissolved in diethyl ether (500 ml). The organic layer was washed with 5% sodium hydroxide (50 ml), dried over MgSO4 and evaporated in vacuo, affording 12 g (96%) of 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-one as a solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:28]>CN(C)C=O>[NH2:28][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CN1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Reactant: N
Solvent: CN(C)C=O
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
In the same manner as described in Example 13, 1-cyclopropyl-5,6,8-trifluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was allowed to react with ammonia in dimethylformamide in a sealed tube to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 254°-255° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([SH:17])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O-])([O-])=O.[Cs+].[Cs+].IC>CC#N>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Sc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CSc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 6-bromo-1-phenyl-1H-indazole-3-thiol (24 g, 78.69 mmol, 1.00 equiv) in CH3CN (200 mL), Cs2CO3 (28.8 g, 88.34 mmol, 1.12 equiv). To the resulting mixture as then added iodomethane (12.6 g, 88.73 mmol, 1.13 equiv) dropwise with stirring at room temperature. The resulting solution was stirred for 60 min at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield 6-bromo-3-(methylthio)-1-phenyl-1H-indazole as a yellow solid. MS: 328 (MH+).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:11]([NH:18][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (3.00 g, 13.51 mmol) in methylene chloride (20 mL) was added benzyl amine (1.60 mL, 14.86 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (6.57 g, 14.86 mmol) and N,N-diisopropylethylamine (4.71 mL, 27.02 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (100 mL), and washed with water (100 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash-chromatography (eluent hexanes-ethyl acetate, 1:1) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide as a yellow solid (3.50 g, 83% yield). MS (M+H)+=312; Rt=1.31 min.
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].O.O.O.O.O.O.O.O.O.O.O.O.OP([O-])([O-])=O.[Na+].[Na+]>O.[OH-].[Na+]>[NH2:7][C@H:6]([C:5]([OH:14])=[O:4])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: *CCO*
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: Cl
Solvent: O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 110 °C

Procedure:
2.42 Grams (10 mmol) of L-histidine methyl ester dihydrochloride, 1.11 g (3.1 mmol) of disodium phosphate 12 hydrate and 0.1 g of polyoxyethylene lauryl ether (“Newcol 1100”, nonionic surfactant produced by Nippon Nyukazai Co., Ltd.) were dissolved in 5.0 ml of water to prepare a treating agent solution. A cotton cloth (150 mm×170 mm, 4.8 g) was in advance treated to be immersed in 25% aqueous sodium hydroxide solution for an hour at room temperature, washed with water and dried. This treated cotton cloth was allowed to uniformly absorb the total amount of the above treating agent solution and then air-dried for 3 hours at room temperature. The dried cloth was heat-treated for 20 minutes at 140° C. in a batch type hot air oven (“IPHH-2000”, an inert oven manufactured by Tabaiesbeck Co., Ltd.) and washed with water. It was further washed with 5% aqueous sodium bicarbonate solution and rinsed three times with water and subsequently washed with 10% aqueous succinic acid solution and rinsed three times with water, and finally washed with household washing detergent solution, rinsed with water and air-dried. The identification of L-histidine cellulose ester was conducted by the following method. A part of the cloth was cut and a solution of ninhydrin in butanol was sprayed on it. Thereafter, it was heated for 10 minutes in an oven of 110° C. to cause coloring thereby the presence of the amino acid was confirmed. Also, a part of the cloth was cut and subjected to an infrared spectroscopic analysis whereby there was confirmed a peak based on ester bond at 1730–1750 cm−1. As a result of determination for the amount of the bonded L-histidine, it was 0.17 mmol based on 1 g of the cloth. The degree of esterfication was 0.028. Also, the amount of succinic acid was 0.18 mmol.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10](Br)Br.CC[OH:15]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10]=[O:15]
Reactant: CCO
Reactant: N#Cc1ccc(Br)c(C(Br)Br)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: N#Cc1ccc(Br)c(C=O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Bromo-3-dibromomethyl-benzonitrile (5.66 g, 16 mmol) was dissolved in EtOH (150 mL) and heated to 60° C. Silver nitrate (6.80 g, 40 mmol), prepared as a solution in H2O (40 mL), was added dropwise, and the reaction was heated to 75° C. and stirred overnight. The organic layer was decanted, concentrated, and filtered, and the residue was partitioned between EtOAc and H2O. The product was extracted with EtOAc, and the combined organic layers were concentrated and purified by silica gel chromatography (0-30% EtOAc in hexanes) to give 4-bromo-3-formyl-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].I[CH3:17]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:17])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred mixture of 22 parts of methyl 2,4-dichlorobenzeneacetate and 135 parts of N,N-dimethylformamide are added 3.1 parts of sodium hydride dispersion 78% while nitrogen gas is introduced. The whole is stirred till foaming has ceased and cooled in an ice-bath. Then there are added dropwise 16 parts of iodomethane. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated, yielding 20 parts (80%) of methyl 2,4-dichloro-α-methylbenzeneacetate as a residue.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:18][NH:17]2)=[O:15])[CH2:12][CH2:11]1)#[N:9].[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:8]([C:10]1([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:18][N:17]2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:15])[CH2:12][CH2:11]1)#[N:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)CN2)CC1
Reactant: O=C(O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)CN2C(=O)c2ccccc2)CC1

Procedure:
L22. (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide trifluoro-acetate from experiment K3 was coupled with benzoic acid in analogy to experiment A1 to give (2S,4R)-4-benzenesulfonyl-1-benzoyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale yellow solid. MS: 424.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[O:6][CH2:5][CH2:4][O:3]1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]([O:11][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])=[O:10])[O:6][CH2:5][CH2:4][O:3]1
Reactant: O=C1CCC(=O)N1O
Reactant: CC1(CCC(=O)O)OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1(CCC(=O)ON2C(=O)CCC2=O)OCCO1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid (8.95 g, 55.9 mmol) in dichloromethane (111 mL) was cooled to approximately 0° C. N-hydroxysuccinimide (7.10 g, 61.5 mmol), 4-methylmorpholine (6.22 g, 61.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.8 g, 61.5 mmol) were sequentially added with stirring. The reaction was then allowed to warm to room temperature, stirred for 17 hours, and partitioned between dichloromethane (150 mL) and water (50 mL). The organic layer was separated; sequentially washed with water (50 mL), saturated aqueous sodium bicarbonate (2×50 μL), and brine (50 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide 13 g of 1-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]oxy}pyrrolidine-2,5-dione as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH:36]1C[CH2:39][CH:38]([OH:41])[CH2:37]1>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][N:35]4[CH2:36][CH2:37][CH:38]([OH:41])[CH2:39]4)=[CH:31][CH:32]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: NC1CCC(O)C1
Product: Nc1ncnn2c(-c3ccc(CN4CCC(O)C4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 4 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 3-amino-cyclopentanol as starting materials, 8.7 mg (4%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.65 (s, 1 H), 3.60 (m, 2 H), 2.85-2.20 (m, 6 H); ES-MS m/z 515.99 [M+H]+, HPLC RT (min) 2.24.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:8]([CH3:26])=[C:9]([CH3:25])[C:10](OS(C(F)(F)F)(=O)=O)=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[O:29][CH3:30].[CH2:31](C([Sn])=C(CCCC)CCCC)[CH2:32]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:8]([CH3:26])=[C:9]([CH3:25])[C:10]([CH:31]=[CH2:32])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COC(=O)c1cc(Cc2ccc(F)c(OC)c2)c(C)c(C)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(F)c(OC)c2)c(C)c1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.63 g) in DMF (7.00 mL) were added tributylvinyltin (0.61 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (0.05 g) and lithium chloride (0.44 g), and the mixture was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.39 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[ClH:40]>C(Cl)Cl>[ClH:40].[NH2:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:24]([NH:23][C:20]2[N:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:25])[CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)C1
Agent: Cl
Solvent: ClCCl
Product: NC1CCCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 1-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidin-3-ylcarbamate (Example 17; 10 mg, 0.018 mmol) was dissolved in 0.1 mL DCM, followed by addition of 0.5 mL 4 N HCl (dioxane) solution in one portion. After stirring at ambient temperature overnight, the reaction was concentrated to yield the final product salt form as a light yellowish solid. MS (apci) m/z=442.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccco1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccco1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mNol) 2-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 413(M+1)
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:14]C>Br>[OH:14][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 2.6 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 26 ml of constant-boiling hydrobromic acid is heated under reflux for 2 hours. After cooling the solvent is distilled in a water-jet vacuum. The crystalline residue is recrystallized from 50 ml of water at boiling temperature. There is obtained 3,4-dihydroxy-5-nitrobenzoic acid in the form of yellow crystals of m.p. 224°-226°.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8](O)=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].CCN(CC)CC.ClC(OCC)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O)C1C=CC=CC=1>CC(C)=O.O>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([N:26]=[N+:27]=[N-:28])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)[C@@H]1C[C@H](C(=O)N=[N+]=[N-])C1(C)C
Reaction time: 3 h
Yield: 100 %

Procedure:
A stirred solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (1.0 g, 5.88 mmol) in acetone (20 ml), Et3N (1.6 ml, 11.76 mmol) and ethyl chloroformate (1.12 ml, 11.76 mmol) were added slowly by portion wise at about 0° C. and stirred for about 3 hours. After completion of the reaction (monitored by TLC), NaN3 (0.84 g, 12.93 mmol) dissolved in minimum amount of water was added to reaction mixture at 0° C. and the reaction mixture was allowed to stir at room temperature for about 1.5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with DCM and washed with water, brine and dried over Na2SO4 and benzyl alcohol (0.95 ml, 8.82 mmol) then the solvent was evaporated and the crude product was processed for next reaction immediately without characterization (considering as 100% yield proceeded for next reaction). Crude wt: 1.147 g (100% yield).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([CH3:42])[C:32]=1[O:33][CH2:34][CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[C:26](=[NH:29])[NH:27]O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCN(C(C)C)C(C)C.CC(=O)OCC>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[N:29]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:27]=2)[CH:30]=[C:31]([CH3:42])[C:32]=1[O:33][CH2:34][CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38]
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: CCOC(COc1c(C)cc(C(=N)NO)cc1Cl)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1Cl)OCC
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (704 mg, 3.18 mmol) in DMF (5 mL) TBTU (1.43 g, 4.45 mmol) and Hünig's base is added. The mixture is stirred at rt for 15 min before 3-chloro-4-(2,2-diethoxyethoxy)-N-hydroxy-5-methylbenzimidamide (907 mg, 2.86 mmol) is added. Stirring is continued for 18 h before another portion of 3-chloro-4-(2,2-diethoxyethoxy)-N-hydroxy-5-methylbenzimidamide (503 mg, 1.59 mmol) and TBTU (510 mg, 1.59 mmol) is added. Stirring is continued for 4 h. The mixture is diluted with EA (100 mL) and washed with water (50 mL). The washing is extracted three times with EA (3×50 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The residue is dissolved in dioxane (35 mL) and the resulting solution is stirred at 110° C. for 18 h. The solvent is evaporated and the crude product is purified by MPLC on silica gel eluting with heptane:EA 7:3 to give 3-(3-chloro-4-(2,2-diethoxyethoxy)-5-methylphenyl)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazole (1.01 g) as a yellow oil; LC-MS: tR=1.43 min, [M+H]+=502.29; 1H NMR (CDCl3): δ 8.06 (d, J=1.9 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.50 (d, J=0.9 Hz, 1H), 7.29 (d, J=1.1 Hz, 1H), 4.94 (t, J=5.3 Hz, 1H), 4.08 (d, J=5.3 Hz, 2H), 4.02 (s, 3H), 3.77-3.86 (m, 2H), 3.64-3.73 (m, 2H), 3.19-3.29 (m, 1H), 2.44 (s, 3H), 2.08-2.14 (m, 2H), 1.83-1.94 (m, 4H), 1.71-1.77 (m, 2H), 1.28 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.[Br:26]N1C(=O)CCC1=O>C1COCC1>[Br:26][C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[C:16]2[O:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: Cn1nccc1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (32 mg, 0.096 mmol) in THF (0.7 mL) was added N-bromosuccinimide (19 mg, 0.10 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. Purification on silica gel using EtOAc/hexane gave the title compound, 24 mg. LCMS calc. for C19H16BrN4O2 (M+H)+: m/z=411.0, 413.0. found: 411.1, 413.1. 1H NMR (300 MHz, DMSO-d6): d 7.40 (s, 1H); 7.31 (m, 3H); 7.13 (m, 2H); 7.08 (s, 1H); 6.30 (s, 1H); 5.50 (s, 1H); 4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10]CC2C=CC=CC=2)=[C:4]1[CH2:18][O:19]C)[CH3:2].[ClH:21]>>[ClH:21].[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([OH:10])=[C:4]1[CH2:18][OH:19])[CH3:2]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: Cl
Product: CCn1ccc(=O)c(O)c1CO
Yield: 73 %

Procedure:
2.0 g (7.33 mmol) 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)one was dissolved in 50 ml of 4N hydrochloric acid and refluxed for 6 hours. Concentration to dryness in vacuo afforded the crude product. Recrystallisation from methanol/diethyl ether gave the pure title compound (1.1 g, 73%) as a white crystalline solid. m.p. 168-169° C.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][CH2:4][O:5][CH2:6][CH:7]=[CH2:8].[ClH:19].[CH3:20]O>>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([O:11][CH3:20])=[O:10])[CH2:3][CH2:4][O:5][CH2:6][CH:7]=[CH2:8].[ClH:19]
Reactant: CO
Reactant: C=CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: C=CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Yield: 98.9 %

Procedure:
A solution of Boc-L-HomoSer(O-allyl)-OH (4.50 g, 17.4 mmol) in HCl/MeOH (50 mL) was stirred at 20° C. for 6 hrs. The solvent was removed at reduced pressure to give Boc-L-HomoSer(allyl)-OMe HCl (3.60 g, 98.9%).