Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[C:12]([O:15][CH2:16]Cl)(=[O:14])[CH3:13]>CC(N(C)C)=O>[C:12]([O:15][CH2:16][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH2:16][O:15][C:12](=[O:14])[CH3:13])[C:5]1=[O:8])(=[O:14])[CH3:13]
Reactant: CC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCn1cc(F)c(=O)n(COC(C)=O)c1=O
Yield: 6.6 %

Procedure:
In 70 ml of dimethylacetamide was dissolved 2.60 g (0.02 mol) of 5-fluorouracil. To this solution were added 0.96 g (0.02 mol) of 50% sodium hydride and then a solution of 2.16 g (0.02 mol) of chloromethyl acetate in 10 ml of dimethylacetamide. The mixture was reacted together at room temperature for 5.5 hours. After completion of the reaction, the reaction liquid was filtered to remove a precipitate and then the dimethylacetamide used as solvent was removed from the filtrate by distillation. The residue was taken up in 100 ml of ether and the ethereal solution was filtered to remove insoluble matters. The ether was removed by distillation and the residue was subjected to an adsorption treatment using a column packed with silica gel. The adsorbed substance was elutriated with a mixture (1:1 in mixing ratio) of benzene and ethyl acetate to isolate at first 180 mg of 1,3-bis(acetoxymethyl)-5-fluorouracil in a yield of 3.2%. This product was a viscous liquid and exhibited in IR-absorption spectral analysis characteristic absorption bands at 3120, 2970, 1755(s), 1704(s), 1690(s), 1478, 1375, 1285, 1230(s), 1170, 1087, 1035(s), 980, 842, 790 and 772 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:17])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Br)=[O:28]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C:27](=[O:28])[CH2:26][Br:25])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: O=C(Br)CBr
Reactant: COC(=O)CCNC(=O)c1cc(I)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1cc(I)ccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
21.0 g (60.5 mmol) of 3-iodo-6-amino-N-(2-methoxycarbonylethyl)benzamide prepared as in Example 1b) were dissolved in 270 ml of dichloromethane, and 12.5 ml (90.7 mmol) of triethylamine were added. At -30° C., 7.8 ml (90.7 mmol) of bromoacetyl bromide in 80 ml of dichloromethane were added dropwise. The mixture was stirred at room temperature for 2 h and then washed with 10% strength citric acid solution and sodium bicarbonate solution, dried and concentrated. The product was recrystallized from dichloromethane, resulting in 26.1 g (92%) of pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(F)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 3-fluoro-4-methoxyaniline (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and isolated as a brown solid (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.82 (br. s., 1H); 8.77 (d, J=7.0 Hz, 1H); 8.34 (br. s., 1H); 7.75 (d, J=14.1 Hz, 1H); 7.18-7.31 (m, 4H); 7.11-7.17 (m, 1H); 7.05 (t, J=9.8 Hz, 1H); 6.89 (t, J=7.4 Hz, 5H); 4.81 (d, J=8.6 Hz, 3H); 3.80 (br. s., 3H); 3.72 (d, J=10.4 Hz, 7H); 2.56 (br. s., 3H). m/z (ESI, +ve ion) 567.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:8](=[O:15])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:23](OC([O-])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>O>[CH2:1]([N:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11][CH2:10]2)[C:8](=[O:15])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(=O)C12CCNCC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCN1C(=O)NC(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of the compound prepared in Example 5 (326 mg) in water (3 mL) were added potassium carbonate and t-butyl dicarbonate (348 mg) subsequently, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous solution of sodium chloride, dried over an anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1→1:2) to give the title compound (419 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH3:16])[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1.B(F)(F)F.CCOCC.[CH3:26][OH:27]>>[CH3:26][O:27][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1OC1(C)c1cccc(OC)c1
Reactant: CO
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)C(O)C(C)(OC)c1cccc(OC)c1
Reaction time: 12 h

Procedure:
19.5 g (88 mmol) of methyl 3-(3-methoxyphenyl)-2,3-epoxybutyrate are dissolved in 200 ml of absolute methanol, and 0.1 ml of boron trifluoride etherate is added. Stirring is carried out for 12 hours at room temperature and the solvent is distilled off. The residue is taken up in ethyl acetate and the solution is washed with sodium bicarbonate solution and water and dried over sodium sulfate. After the solvent has been distilled off, 21.1 g of a slightly yellow oil remain.
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].C[N+](C)(C)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CN(C)C=O>[C:17]1([C:9]2[NH:10][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:16]3[C:8]=2[CH2:7][C:1]#[N:2])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [C-]#N
Reactant: C[N+](C)(C)Cc1c(-c2ccccc2)[nH]c2nccnc12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c(-c2ccccc2)[nH]c2nccnc12
Temperature: 75 °C

Procedure:
A solution of potassium cyanide (0.84 g) in water (20 mL) was added rapidly to a stirred solution of trimethyl(6-phenyl-5H-pyrrolo[2,3-b]pyrazin-7-ylmethyl)-ammonium iodide [1.1 g, Reference Example 33] in dimethylformamide (20 mL) and the mixture heated at 75° C. for 6 hours. The cooled solution was diluted with water (100 mL) and the precipitated solid filtered to give the title compound as a yellow solid, m.p. 247–248° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:19](#[N:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]1=[N:12][C:11]([CH3:13])=[N:10][N:9]1[C:19]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:26]
Reactant: Cc1nc(-c2ccc(Cl)cc2)n[nH]1
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 0 °C
Yield: 49.1 %

Procedure:
2.0 g (10.3 mmol) of 3-(4-Chlorophenyl)-5-methyl-1,2,4-triazole is dissolved in 50 ml of tetrahydrofuran (THF) (freshly distilled from lithium aluminum hydride) mechanically stirred in a 250 ml round-bottom 3-necked flask equipped with a septum and nitrogen inlet and cooled in an ice bath. 13.6 ml (22.7 mmol) of n-butyllithium (1.67 mol/liter in hexane) is injected with a syringe and the mixture is stirred in the ice bath for 30 minutes. 2.12 g (20.6 mmol) of benzonitrile is added in a little THF. After stirring for 30 minutes in the ice bath and for 30 minutes at room temperature, the mixture is poured into a chilled stirred mixture of 100 ml of 2.5 M ammonium chloride and 200 ml of chloroform. The layers are separated and the aqueous layer washed with chloroform. The combined chloroform layers are washed with water and dried (Na2SO4). The chloroform is removed under vacuum and the residue is recrystallized from toluene to yield 1.5 g of the title compound, m.p. 173°-175°.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][C:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:12])(=O)=O.O.ClCCl>CS(C)=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:11]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([CH3:12])[CH2:10][CH2:9][C:1]#[N:2])=[CH:30][CH:29]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(C)(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
128 mg (1.96 mmol) of potassium cyanide were added to 430 mg (0.98 mmol) of the compound from Example 114A in 8 ml of DMSO. The mixture was stirred at 80° C. for 8 h, water and dichloromethane were added to the reaction solution, and the phases were separated. The organic phase was extracted with dichloromethane, and the combined organic phases were freed of solvent. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 280 mg (77% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1)[CH3:2].[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:14]([C:12]2[N:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])[O:10][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:16])=[CH:30][CH:31]=1
Reactant: CCc1ccccc1-c1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCc1ccccc1-c1nc(C(=O)Nc2ccc(N(C)CCOC)nc2)c(C(F)(F)F)o1

Procedure:
With a procedure similar to example 16 above, 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H23F3N4O3 (m/e) 448, obsd 449 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][CH:14]2[CH3:19].C1C(=O)N([I:29])C(=O)C1>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([I:29])[CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][CH:14]2[CH3:19]
Reactant: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccc(I)cc1Cl
Yield: 21.1 %

Procedure:
A solution of 7-(2-chlorophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (18 mg, 0.059 mmol), NIS (17 mg, 0.074 mmol), and p-TsOH-H2O (24 mg, 0.12 mmol) in THF-MeOH (1 mL/1 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford 7-(2-chloro-4-iodophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (5.4 mg, 21%). MS APCI (−) m/z 433, 435 (M-, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.70 (d, 1H), 7.48 (dd, 1H), 6.75 (m, 2H), 6.04 (s, 1H), 4.63 (q, 1H), 1.49 (d, 3H).
Reaction SMILES: [H-].[Na+].CN([CH:6]=[O:7])C.CO.[Cl:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3>O>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH3:6])[CH:14]=[CH:13][C:12]=1[C:18]1[C:31](=[O:32])[N:30]([CH3:33])[C:21]2[N:22]([CH3:29])[C:23]3[C:28]([C:20]=2[CH:19]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: Cn1c(=O)c(-c2ccc(F)cc2Cl)cc2c3ccccc3n(C)c21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc3c4ccccc4n(C)c3n(C)c2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
3.25 g (81.1 mmol) of 60% NaH are added to 300 ml of DMF and 9.6 ml of MeOH. The mixture is left to stir for 5 minutes, and then 9.22 g (27.0 mmol) of compound A 3-(2-chloro-4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are added. The mixture is stirred at ambient temperature and then, as soon as no more gas is being given off, is heated at 80° C. for 16 h. The reaction medium is left to cool and poured into H2O, the yellow precipitate is filtered off and washed with H2O, the residue is taken up in MeOH and the product is concentrated to dryness.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][CH2:15][O:16][CH3:17])=[C:10]([NH:19][CH2:20][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])([CH3:23])[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N.ClC1C(NC(=O)CCOC)=C(CC(NS(C)(=O)=O)(C)C)C2C(=CC=CC=2)[N:32]=1>CO>[NH2:32][C:2]1[C:11]2[N:12]=[C:13]([CH2:14][CH2:15][O:16][CH3:17])[N:19]([CH2:20][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])([CH3:22])[CH3:23])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCC(=O)Nc1c(Cl)nc2ccccc2c1CC(C)(C)NS(C)(=O)=O
Reactant: COCCC(=O)Nc1c(Cl)nc2ccccc2c1NCC(C)(C)NS(C)(=O)=O
Agent: N
Solvent: CO
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 170 °C
Yield: 167.2 %

Procedure:
A Parr bomb was charged with 25.0 g of N-{2-chloro-4-[2-(methanesulfonylamino)-2-methylpropyl]aminoquinolin-3-yl}-3-methoxypropionamide and ammonia in methanol (300 mL of 7 N). A second vessel was charged with 30.21 g of N-{2-chloro-4-[2-(methanesulfonylamino)-2-methylpropyl]quinolin-3-yl}-3-methoxypropionamide and ammonia in methanol (400 mL of 7 N). Both vessels were sealed and then heated at 170° C. for 14 hours. The reaction mixtures were combined and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 38.16 g of N-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as an off white foam.
Reaction SMILES: Cl.[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4].[BrH:19]>>[BrH:19].[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCN1CCCC(c2cccc(OC)c2)C1
Agent: Br
Agent: Cl
Product: CCCN1CCCC(c2cccc(O)c2)C1
Yield: 86 %

Procedure:
N-Propyl-3-(3-methoxyphenyl)piperidine hydrochloride (7.0 g, 0.026 mol) was suspended in 48% HBr (200 ml). The mixture was refluxed under nitrogen for 3 h. The hydrobromic acid was evaporated and the residue was recrystallized from ethanol/ether, yielding the pure product (6.7 g, 86%) mp. 146°-7.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C)C=O>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][N:8]1[CH:7]=[C:6]2[C:10]([CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[N:9]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1cc2cc([N+](=O)[O-])ccc2n1)OC
Temperature: 55 °C
Reaction time: 12 h
Yield: 23.4 %

Procedure:
To mixture of 3.00 g (18.4 mmol) of 5-nitroindazole and 5.08 g (36.9 mmol) of K2CO3 in 61 mL of N,N-dimethylformamide and was added 3.42 g (20.2 mmol) of 2-bromo-1,1-dimethoxy-ethane. The mixture was heated to 55° C. and allowed to stir for 12 hours. The reaction mixture was cooled to room temperature and the contents filtered through a bed of celite. The filtrate was then concentrated under reduced pressure and the residue purified via column chromatography (30–80% ethyl acetate/hexanes) to provide 1.08 g of the title product. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.31 (s, 6 H), 4.67 (d, J=5.49 Hz, 2 H), 4.91 (t, J=5.42 Hz, 1 H), 7.81 (m, 1.92 Hz, 1 H), 7.98 (m, 1 H), 8.62 (m, 2 H); MS (DCI/NH3) m/z 252 [M+H]+.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[I:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.O>CN(C)C=O>[I:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][Si:5]([CH3:7])([CH3:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
387 mg of irdidazole and 411 mg of tertbutyldimethylsilyl chloride is added at ambient temperature and under an inert atmosphere to 500 mg of para-iodo-phenol in 4 ml of dimethylformamide and the mixture is maintained under agitation for 15 hours at ambient temperature then for 1 hour at 40° C. The reaction medium is poured into water, and the aqueous phase is extracted with dichloromethane. The organic phase is then dried and evaporated under reduced pressure. In this way 636 mg of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][S:8][C:9]2[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[N:31]([C:10]1[C:9]([S:8][CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:11]=1[F:27])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (24.18 g, 53.75 mmol) in DMF (200 mL) was added NaN3 (4.19 g, 64.49 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (pale yellow solid, 21.63 g, 85.1% yield). 1H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 7.80 (s, 1H), 7.33 (m, 4H), 7.15 (m, 1H), 6.90 (m, 1H), 6.85 (m, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([NH:9][N:10]([CH2:36][CH2:37][C:38]([O:40]CC1C=CC=CC=1)=[O:39])[C:11]([N:13]1[C@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][CH2:15][N:14]1C(OCC1C=CC=CC=1)=O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[C:1]([NH:9][N:10]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:11]([N:13]1[C@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)N1C(=O)N(CCC(=O)OCc1ccccc1)NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCCNN1C(=O)N(CCC(=O)O)NC(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
A solution of 260 (1.59 g, 2.47 mmol) in MeOH (142 ml) was treated with 10% Palladium on carbon (230.0 mg) and stirred under an atmosphere of H2 for 1.5 h. The mixture was filtered and the solvent evaporated to afford 1.04 g (100%) of a white foam. This was used in the next step without further purification: mp <40° C.; [α]D26 +1.6° (c 0.26, CH2Cl2); IR (KBr) 3422, 2977, 2986, 1728, 1677, 1486, 1445, 1396, 1369, 1309, 1228, 1155, 916, 716; 1H NMR (CDCl3) δ 10.0-9.7 (1H, brm), 7.86 (2H, d, J=7.5), 7.62-7.38 (3H, m), 7.3-5.6 (2H, brm), 4.57 (1H, brd, J=4.0), 4.05-3.77 (2H, m), 3.00-2.82 (1H, m), 2.80-2.43 (3H, m), 2.20-2.03 (1H, m), 2.00-1.47 (1H, m), 1.62-1.14 (11H, m); 13C NMR (CDCl3) δ 175.00, 171.17, 167.62, 160.68, 132.39, 131.77, 128.67, 127.38, 82.27, 54.38, 48.04, 46.35, 33.62, 28.02, 25.68, 21.61. MS (ES+) 443 (M+Na, 68%), 421 (M++1), 100), 365 (50), 131 (61).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:20](OCC)=[O:21])[NH:18][N:19]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH2:20][OH:21])[NH:18][N:19]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CO)[nH]n2)cc1
Reaction time: 1 h
Yield: 87 %

Procedure:
With cooling with ice, 890 mg (18.8 mmol) of lithium aluminium hydride was added to a tetrahydrofuran solution (30 ml) of 2.31 g (9.4 mmol) of the obtained ethyl 5-(4-methoxyphenyl)-2H-pyrazole-3-carboxylate, and the reaction liquid was stirred for 1 hour with cooling with ice. Aqueous 2 N sodium hydroxide solution was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.67 g (yield: 87%) of [5-(4-methoxyphenyl)-2H-pyrazol-3-yl]-methanol as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=O.O.[NH2:14][NH2:15]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:15][NH:14][C:5]2=[O:6]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Yield: 72.3 %

Procedure:
A mixture of 5-Bromo-isobenzofuran-1,3-dione (6.0 g, 26.4 mmol) and hydrazine hydrate (1.51 mL, 32.4 mmol) in isopropanol (120 mL) was heated at reflux for 4 h. The mixture was allowed to cool and the precipitate was filtered and washed with water (50 mL). The filter cake was dried to afford the title compound (4.6 g, 72.3%) as a white solid. m/z (M+1)=241.05
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CS(O)(=O)=O>O1CCOCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:7]3[CH:8]=[CH:9][NH:10][C:6]=3[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cnc(Cl)c2cc[nH]c12
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2cccc(Cl)c2)c2cc[nH]c12

Procedure:
A mixture of ethyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.49 g), 3-chloroaniline (0.46 ml) and methanesulfonic acid (0.28 ml) in 1,4-dioxan (10 ml) was irradiated at 180° C. for 30 minutes with microwaves. The residue was partitioned between ethyl acetate and water, the aqueous layer was separated, basified with an aqueous 2M sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown solid (0.91 g).