Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.Cl[CH2:14][Cl:15].OC[C@@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1.[Cl-].[Li+]>O.CN(C)C=O>[Cl:15][CH2:14][C@@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(I)cc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CCl)Cc1ccc(I)cc1
Reaction time: 0.5 h

Procedure:
0.27 ml (1.92 mmol) of triethylamine and 165 mg (1.44 mmol) of methanesulfonyl chloride were added to 5 ml of dichloromethane containing 360 mg (0.96 mmol) of t-butyl [(1S)-2-hydroxy-1-(4-iodobenzyl)ethyl]carbamate under cooling with ice. After stirring for 30 minutes, the temperature was elevated to room temperature, and the mixture was stirred for 15 hours. The reaction liquid was diluted with water. After the extraction with dichloromethane, the organic layer was successively washed with 1 N hydrochloric acid, 1 N sodium hydroxide and saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. 10 ml of dimethylformamide and 203 mg (4.8 mmol) of lithium chloride were added to the residue, and they were stirred at 50° C. for 19 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]#[N:41])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][C:40]#[N:41])=[CH:35][CH:34]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2C1CCCC1
Yield: 62.5 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (160 mg) obtained in Step C of Example 12, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (160 mg), tetrakis(triphenylphosphine)palladium(0) (50.6 mg) and 2M aqueous sodium carbonate solution (1.10 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (91.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:24])=[O:12])=[CH:5]2.C[O-].[Na+].Br[CH2:29][C:30]#[N:31].Cl>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:29][C:30]#[N:31])[C:15]1=[O:24])=[O:12])=[CH:5]2
Reactant: O=C(N[C@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N#CCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Yield: 26.8 %

Procedure:
(S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 4, 13.4 mg) was dissolved in tetrahydrofuran (5 mL) at room temperature under argon with stirring. After cooing to 0° C., sodium methoxide (4.3 mg) was added, followed 2 h later by bromoacetonitrile (7.2 mg). This was warmed to room temperature over 2 h, and 2 h later water (15 mL), 1.0 M aqueous hydrochloric acid (1 mL), and ethyl acetate (20 mL) were added. The organic phase was separated, washed with brine, and dried over anhydrous sodium sulfate. After solvent evaporation under vacuum, the crude product was purified by reverse phase preparative HPLC to provide the title compound (4 mg). HPLC/MS [M+H]+, 379; HPLC/MS [M+Na]+, 401.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1C=C(OC)C=CN=1)=[O:4].ClC1N[C:16]2[CH:22]=[CH:21]C=CC=2N=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:2][CH:3]([OH:4])[CH3:5].[CH:3]([O:4][CH:22]([CH3:21])[CH3:16])([CH3:5])[CH3:2]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1ccnc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)O
Product: CC(C)OC(C)C
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
2-Bromoacetyl-4-methoxypyridine (11.5 g, 0.05) and 2-chlorobenzimidazole (7.5 g, 0.05 mole) were dissolved in dimethylformamide (75 ml) and cooled to 2° C. K2CO3 (12 g, 0.08 mole) was added and the temperature rose to 9° C. as the suspension was stirred for 1/2 hour. The mixture was added to H2O (200 ml) giving a solid which was removed by filtration. The mother liquors were extracted with ethyl acetate and the solid was dissolved in the extracts. The organic solution was washed (brine) and dried (MgSO4) and purified by passage down a silica column and evaporated to dryness to give a sticky solid. Trituration with propan-2-ol/di-isopropyl ether gave 2-chloro-1-[2-(2-[4-methoxypyridyl])-2-oxoethyl]-benzimidazole (7.2 g).
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH3:21])[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:13]=2[C:12]([CH3:38])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CN(C)C=O.[OH-].[OH-].[Pd+2]>[CH2:18]([C:15]1[N:14]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:13]2[C:12]([CH3:38])=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=1)[CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCc1nc2c(OCc3ccccc3)ccc(C)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1nc2c(O)ccc(C)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 57 from 4-'-[(4-benzyloxy-2-n-butyl-7-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and hydrogen in methanol/dimethylformamide in the presence of 20% palladium hydroxide on carbon.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.NC1N=NC=CN=1>ClC(Cl)Cl>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[NH:21][CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Agent: Nc1nccnn1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c[nH]c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
A mixture of 11.3 g of ethyl 2-(2,7,-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 5.65 g of 3-amino-1,2,4-triazine in 60 cm3 of trichloromethane is stirred for 16 hours at a temperature close to 20 C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at a temperature close to 30° C. The residue is taken up in 60 cm3 of ethanol and 5.6 g of DBU and the mixture is heated at a temperature close to 75° C. for 20 hours. After cooling to 20° C., the insoluble matter is drained and washed with twice 40 cm3 of ethanol. 6.1 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo [b][1,8]naphthyridine are obtained in the form of a brown solid which decomposes at 378°-380° C. and which can be used for the subsequent steps without further purification.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[CH3:12])=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2.C(O)C.N1CCCC1>C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])/[C:17]/2=[CH:1]\[C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[CH3:12]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Scale-Up Procedure. 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (61 g), 5-fluoro-1,3-dihydro-indol-2-one (79 g), ethanol (300 mL) and pyrrolidine (32 mL) were refluxed for 4.5 hours. Acetic acid (24 mL) was added to the mixture and refluxing was continued for 30 minutes. The mixture was cooled to room temperature and the solids collected by vacuum filtration and washed twice with ethanol. The solids were stirred for 130 minutes in 40% acetone in water (400 mL) containing 12 N hydrochloric acid (6.5 mL). The solids were collected by vacuum filtration and washed twice with 40% acetone in water. The solids were dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (86 g, 79% yield) as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[C:32]([O:34][CH3:35])=[O:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
To a suspension of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoic acid (2.26 g, 6.68 mmol) in DCM (50 mL) was added (R)-methyl piperidine-2-carboxylate HCl salt (1.00 g, 5.57 mmol), followed by EDC (1.60 g, 8.35 mmol), HOBT (1.71 g, 11.1 mmol), and TEA (2.33 mL, 16.7 mmol). The reaction mixture was stirred at rt for 6 hr. The reaction mixture was diluted with water and extracted with EtOAc (2×30 mL). The combined EtOAc layers were washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 30-70% EtOAc/Hex to give (R)-methyl 1-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoyl)piperidine-2-carboxylate (1.80 g, 3.88 mmol, 69.8% yield) as a white foam. Anal. Calcd. for C23H33N3O7 m/z 463.5. found: 464.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][CH:12]=1)=[O:9].[Br:21]NC(=O)CCC(N)=O>C(#N)C>[Br:21][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[NH:10][C:8]([NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=C(Nc1cnccn1)Nc1ccnc2ccccc12
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: O=C(Nc1cnccn1)Nc1c(Br)cnc2ccccc12
Yield: 79 %

Procedure:
1-(Pyrazin-2-yl)-3-(quinolin-4-yl)urea (220 mg, 0.754 mmol) was dissolved in acetonitrile (3 mL) and N-bromosuccinamide was added (201 mg, 1.13 mmol). The resulting solution was heated at 80 C under microwave irradiation for 35 mins. The cooled solution was then partitioned between NaHCO3 solution and dichloromethane. The organic layer was separated, dried (MgSO4), filtered and concentrated to give the product. Yellow solid. Amount 204 mg. Yield 79%.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[N:10]=[N:11][N:12]([CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:13]=1)=[O:6])([CH3:4])[CH3:3].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26].C1COCC1>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([CH:8]([C:9]2[N:10]=[N:11][N:12]([CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:13]=2)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CC(C)(C)S(=O)/N=C/c1cn(C[Si](C)(C)C)nn1
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC(c1ccc(F)c(F)c1)c1cn(C[Si](C)(C)C)nn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a 25 ml round bottom flask containing −78° C. solution of 2-methyl-N-((1E)-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methylene)propane-2-sulfinamide (0.286 g, 0.998 mmol) in 4.0 ml of CH2Cl2 was added dropwise 0.5N 3,4-difluorophenylmagnesium bromide in THF (4.990 ml, 1.495 mmol). The resulting solution was stirred at −78° C. for 30 min, then −20° C. for 16 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (0.498 g, 93% crude). ES-MS [M+1]+: 401.1. This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[S:9][C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1.ClC1C=C(C=CC=1)C(OO)=[O:25]>CC(C)=O.O>[NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[S:9](=[O:25])[C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)Oc1ccc(-c3nnn[nH]3)cc1S2
Solvent: O
Solvent: CC(C)=O
Product: O=S1c2ccccc2Oc2ccc(-c3nnn[nH]3)cc21

Procedure:
2-(5-Tetrazolyl)phenoxathiin (0.70g) and m-chloroperoxybenzoic acid (0.45g) were stirred for 2 hours at room temperature in acetone (20 ml.) and water (5 ml.). The reaction mixture was diluted with water, and the solid filtered, dried, washed with ether and re-dried to give 2-(5-tetrazolyl)phenoxathiin-10-oxide m.p. 267°-8° C. Recrystallisation from glacial acetic acid raised the melting point to 280°-1° C.
Reaction SMILES: C([O-])=O.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:16].[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25]O)=[CH:20][N:19]=1.Cl>C(O)(=O)C>[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([CH2:25][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([OH:16])=[C:6]([O:5][CH3:4])[CH:15]=2)=[CH:20][N:19]=1
Reactant: COc1ccc2ccccc2c1O
Reactant: Nc1ncc(CO)c(N)n1
Agent: Cl
Agent: O=C[O-]
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)c2ccccc2c1O
Yield: 31.5 %

Procedure:
The formate of 2-methoxy-1-naphthol (J. E. Oatis, Jr., M. P. Russell, D. R. Knapp and T. Walle, J. Med. Chem. 1981, 24, 309) (7.23 g, 30.3 mmol), 2,4-diamino-5-hydroxymethylpyrimidine (4.35 g, 30.3 mmol), concentrated hydrochloric acid (4.2 mL) and glacial acetic acid (60 mL) were refluxed 2 hr. The resulting dark solution was evaporated to dryness and the residue dissolved in water and neutralized with ammonia. The resulting tan precipitate (5.2 g) was recrystallized from aqueous ethanol containing a slight excess of hydrochloric acid to give title compound as tan powder (2.83 g, 28%); mp ca. 290°-300° dec. Anal. Calcd for C16H16N4O2.HCl: C, 57.75; H, 5.15; N, 16.84; Cl, 10.65. Found: C, 57.62; H, 5.21; N, 16.79; Cl, 10.61.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][C:12]1([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]1[CH:14]=[N:15][OH:16]
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Reactant: Clc1cccc(C=CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(OC2(CC=Cc3cccc(Cl)c3)C=CC=CC2C=NO)n1
Yield: 61.2 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.6 g of 3-chlorocinnamyl bromide were dissolved in 30 ml of dry acetone containing 2.7 g of anhydrous potassium carbonate. The solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetone was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate:4:1) to obtain 5.2 g of 0-(3-chlorocinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as a semi-solid substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCOCC>C1COCC1>[Br-:1].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1ccc(Br)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 129.7 %

Procedure:
To a solution of 1-bromo-2-(bromomethyl)-4-chloro-benzene (3.00 g, 10.55 mmol) in THF (50 mL) was added triphenylphosphane (4.15 g, 15.82 mmol) and the solution was stirred at room temperature for 20 h. During this time a white solid precipitated. Reaction mixture was filtered to give a white solid, which was slurried with ether and filtered to afford the title compound as a white solid (3.74 g, 65%). MS m/z: 467.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:11][S:12](O)(=[O:14])=[O:13].O=S(=O)=O>>[OH:1][C:2]1[N:10]=[CH:9][C:8]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccnc1O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(S(=O)(=O)O)cnc1O
Temperature: 140 °C
Yield: 82.9 %

Procedure:
2-Hydroxynicotinic acid (27 Kg, 194.2 mol) was added portionwise to 30% oleum (58.1 Kg) at 50° C. over 1 hr. This caused an exotherm to 82° C. The reaction mixture was heated further to 140° C. After maintaining this temperature for 12 hrs the reactor contents were cooled to 15C and filtered. The filter cake was then re-slurried with acetone (33 Kg) at room temperature, filtered and dried to afford the sub-title compound (35.3 Kg, 83%) as a white solid. Decomposition pt 273° C. δ (DMSOd6): 7.93 (1H, d), 8.42 (1H, d). m/z (Found:220 [M+H]+, 100%. C6H6NO6S requires 220.17).
Reaction SMILES: O[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:12](=[O:25])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:12](=[O:25])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]=12
Reactant: CCOc1ccc(-n2c(=O)c3c(O)[nH]c4ccccc4n-3c2=O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOc1ccc(-n2c(=O)c3c(Cl)[nH]c4ccccc4n-3c2=O)cc1

Procedure:
A solution of 4-Hydroxy-2-(4-ethoxyphenyl)-imidazo[1,5,a]-quinoxaline-1,3(2H,5H)-dione (3.2 g) in phosphorous oxychloride (40 mL) was refluxed for 16 h. The solvent was removed in vacuo and water (15 mL) was added. The pH was adjusted to 7.0 using ammonium hydroxide and this resulting solid was filtered and dried to yield 4-Chloro-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 36).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:19][C:17]1[O:16][N:15]=[C:14]([CH3:13])[CH:18]=1
Reactant: Cc1cc(C)on1
Reactant: BrCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(CCCCCCCBr)on1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 46.1 ml of diisopropylamine in 100 ml of tetrahydrofuran at 0°-5° C. was added 126 ml of 2.6M n-butyllithium in hexane over a period of about 20 minutes. The mixture was cooled to -50° C., 31.95 g of 3,5-dimethylisoxazole was added and the mixture stirred for 30 minutes. The latter mixture was cooled to -78° C. and 101.6 ml of 1,6-dibromohexane was added dropwise. After the addition was complete, the temperature of the reaction mixture was allowed to rise to room temperature and kept there for about 40 hours. Saturated aqueous ammonium chloride solution was then added and the mixture extracted with ethyl acetate. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was distilled to remove excess dibromide (b.p. 50° C., 0.5 mm) and suspended in hexane. The suspension was decolorized with charcoal, filtered and cooled in a refrigerator overnight. The mixture was filtered and the filtrate concentrated in vacuo to give 57 g of 5-(7-bromoheptyl)-3-methylisoxazole as a colorless oil.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6].N([O-])=O.[Na+].[N-:28]=[N+:29]=[N-].[Na+].Cl>CC(O)=O.O>[ClH:1].[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]=[N+:28]=[N-:29])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(N)c(I)c2)C[C@@H]2CC[C@H]1N2C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H]1[C@@H](c2ccc(N=[N+]=[N-])c(I)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 3β-[3'-iodo-4'-aminophenyl]tropan-2β-carboxylic acid methyl ester dihydrochloride (1a) (90 mg, 0.1902 mmol) in 1 mL of AcOH (3M) was added an aqueous solution of NaNO2 (17.3 mg, 0.2661 mmol, in 0.5 mL of H2O) at 0° C. After 30 min at this temperature NaN3 (19 mg, 0.2754 mmol) in 0.5 mL of H2O was added dropwise to the reaction mixture and stirred for 30 min at 0° C., then 30 min at room temperature. After removal of all solvent by evaporation, the residue was dissolved in CHCl3 and washed with H2O. The organic layer was dried over MgSO4 and concentrated to give an oil which was converted to HCl salt to yield 64 mg (72.7%) of 3β-[3'-iodo-4'-azidophenyl]tropan-2β-carboxylic acid methyl ester hydrochloride (1b) as a yellowish solid: mp 140°-143° C.; [α]25 -97.4° (c 0.115), MeOh); 1HNMR (250MHz, CDCl3) δ1.51-1.73 (m, 3) 2.07-2.16 (m, 2), 2.19 (s, 3, NCH3) 2.47 (m, 1), 2.80-2.93 (m, 2), 3.32 (m, 1, H-5), 3.51 (s, 3, OCH3), 3.54 (m, 1, H-1), 7.01 (d, 1, J-7.7, ArH), 7.28 (dd, 1, J=7.77, J=1, ArH), 7.60 (d, 1, J=1, ArH).