Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][C:11]23[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2NO)[CH:5]=[CH:6][CH:7]=1.O.[NH2:25]N>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH2:25])[C:11]23[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: ONC1CCCCC12C=Nc1ccc(-c3cccc(Cl)c3)cc12
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(-c3cccc(Cl)c3)cc2C12CCCCC2
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 65.2 %

Procedure:
To a turbid solution of 5′-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3 -[3H]indol]-2-amine (0.500 g; 1.53 mmol) in 25 mL of ethanol was added hydrazine hydrate (0.600 mL; 12.24 mmol). The solution was warmed to 55° C., where Raney-nickel (50% in water) was added to the reaction to keep a constant evolution of gas. After 45 minutes, the hot reaction mixture was filtered through a Celite plug and rinsed with a copious amount of hot methanol. The filtrate was concentrated in vacuo to give 0.890 g of an opaque solid. The product was purified by flash silica gel chromatography, (eluant, 2% to 8% methanol-methylene chloride with 0.1% ammonium hydroxide) to afford 0.310 g (65%) of the desired product as a white solid. Mp. 118-120° C. 1H NMR δ (300 MHz, DMSO-d6) 1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H), 7.1 (br, 2H 2NH), 7.31-7.34 (dt, 1H, J=8 Hz), 7.41-7.46 (t, 2H), 7.55-7.58 (d, 1H), 7.62 (s, 1H), 7.72 (s, 1H); MS (ECI(+ve)) m/z 311 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([CH2:19][CH3:20])(O)[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([CH2:16][CH3:17])([C:23]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=3)[CH2:19][CH3:20])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(O)(CC)CC)cc2s1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a mixture of 6-(1-ethyl-1-hydroxy-propyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.650 g, 2.23 mmol and o-cresol (0.480 g, 4.45 mmol) in CH2Cl2 (20 mL) at −78° C. is added BF3-Et2O (0.316 g, 2.23 mol). After stirring for 10 min, the reaction mixture is allowed to warm to 0° C. over 30 min. The reaction is quenched with water (15 mL) and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography to give the title compound (0.780 g, 92%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C(=O)CC)(=[O:12])[CH2:10][CH3:11].Cl(O)(=O)(=O)=O>>[C:1]([O:8][CH:1]([O:13][C:9](=[O:12])[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:2][CH3:3]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=Cc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(=O)OC(OC(=O)CC)c1ccccc1

Procedure:
Benzaldehyde (1.5 mol) and propionic anhydride (1.5 mol) were reacted in the presence of 0.5 ml perchloric acid by the procedure of Example 4. The resulting benzylidene bispropionate distilled at 104° C (0.1 (mm/Hg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>ClCCl>[N:15]1([C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[S:14])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: S=C(N1CCN(c2ccccn2)CC1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione (or intermediate 3 above) was formed as follows. N-(2-pyridyl)piperazine (MW 163.22, 0.91 ml, 6.0 mmoles, 1 eq) 2 was added to a solution of 1,1′-thiocarbonyldiimidazole (MW 178.22, 1.069 g, 6.0 mmoles, 1 eq) 1 in 50 ml of dichloromethane at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was washed with water, dried over sodium sulfate, filtered and concentrated to provide imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione (MW 273.36, 1.354 g, 4.95 mmol, 83% yield) 3, which was used without further purification. TLC (CH2Cl2/MeOH: 95/5): Rf=0.60, Product UV and Ninhydrin stain active. 1H-NMR (400 MHz, CDCl3), δ ppm: 3.72 (s, 4H), 4.02 (s, 4H), 6.67 (d, 1H, J=7 Hz), 6.72 (dd, 1H, J=7 and 5 Hz), 7.11 (s, 1H), 7.24 (s, 1H), 7.54 (t, 1H, J=7 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J=5 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:24])=[CH:22][C:17]=4[N:16]=[CH:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[H-].[Na+].F[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[O:1][CH2:2][CH:3]1[CH2:4][CH:5]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:24])=[CH:22][C:17]=4[N:16]=[CH:15]3)=[CH:12][CH:13]=2)[CH2:6]1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OC2CC(CO)C2)cc1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OC2CC(COc3ccccn3)C2)cc1
Temperature: 60 °C

Procedure:
1-(4-{[3-(Hydroxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (33 mg, 0.08 mmol) was dissolved in DMF and put under N2 atmosphere. Sodium hydride (2 mg, 0.08 mmol) was added and the reaction was heated to 60° C. 2-Fluoropyridine was then added and the reaction was then heated to 80° C. for 14 h. The reaction was cooled to rt and concentrated in vacuo. The crude solid was purified using the Waters mass-directed HPLC purification system to provide 1-(4-{[3-(2-pyridyloxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as an off-white solid. MS (ES+): m/z 507 (10) [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O-])=O.C(N(C(C)C)CC)(C)C>CC(O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Oc2cc(Nc3ccc(O)cc3)ncn2)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
4-Chloro-6-(4nitro-phenoxy)pyrimidine (Stage 22.5; 3 g, 11.9 mmol), 4-nitrophenol (1.95 g, 17.9 mmol), and diisopropylethylamine (DIPEA) (3.04 ml, 179 mmol) dissolved in 2-propanol (50 ml) are stirred at 85° C. for 18 h. After concentrating the reaction mixture under reduced pressure, the product precipitates as a colorless fine solid: M+H=245.0; 1H-NMR (400 MHz, DMSO-d6): 9.40/9.25 (s/s, 2H, NH/OH), 8.28 (d, 7.5 Hz, 2H, phenyl-NO2), 8.26 (s, 1H, pyrimidinyl), 7.40 (d, 7.5 Hz, 2H, phenyl-NO2), 7.24 (d, 8.0 Hz, 2H, phenyl-OH), 6.77 (d, 8.0 Hz, 2H, phenyl-OH), 6.15 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=2:1): 0.48.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[Cl:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:18][CH2:17][CH2:16][Cl:15])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(=O)c2ccc(O)cc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 51 %

Procedure:
A mixture of 2.43 g (13 mmol) of 2-cyano-7- hydroxy-4-oxo-4H-1-benzopyran, 2.04 g (13 mmol) of 3-chlorobromopropane and 1.80 g (13 mmol) of potassium carbonate was refluxed in 250 ml dry acetone overnight with heating. After evaporating to dryness, the residue was extracted with chloroform (3×100 ml), and dried with sodium sulfate. The chloroform solution was evaporated to one-third of the original volume to which was added n-hexane. The white precipitate was collected by filtration, washed with n-hexane and dried in vacuum to obtain 2-cyano-7-(3-chloropropyloxy)-4-oxo-4H-1-benzopyran (yield 51%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].Cl.N1C=CC=CC=1>O>[CH2:11]([C:4]1[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CCCc1c(OC)cccc1OC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCc1c(O)cccc1O
Temperature: 180 °C
Reaction time: 7.5 h
Yield: 133.1 %

Procedure:
A mixture of solid 1,3-dimethoxy-2-propylbenzene (33.70 g, 190 mmol) and solid pyridine hyrochloride (150 g, 1.30 mol) were warmed to 180° C. After 7.5 hours, the reaction was cooled to 110° C. and 50 mL of H2O was added slowly. After the reaction cooled to room temperature, it was diluted with 100 mL of water and extracted several times with EtOAc. The EtOAc extract was washed once with 2N HC1 and then dried over MgSO4. Filtration and solvent removal gave 38.5 g of an orange solid. The product was purified by recrystallization from dichloromethane providing 11.86 g (41%) of yellow crystals.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(N)c1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(C#N)s2)c1
Reaction time: 0.25 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (8-5, 5.94 g, 24.9 mmol) was dissolved in 50 mL anhydrous THF under N2. NaH (60% suspension, 2.99 g, 74.8 mmol, 3 equiv) was added (vigorous bubbling occurs) and the resulting mixture was stirred for 15 min. 2-Chloro-thiazole-5-carbonitrile (4.32 g, 29.9 mmol) was added and the reaction was heated to reflux. After 2 h the reaction was cooled and was quenched by the addition of water. The THF was removed in vacuo and the resulting aqueous solution was adjusted to pH=7 by the addition of 1M HCl (aq). The resulting precipitate was filtered and washed with water to provide reasonably pure desired product. 1H NMR (CDCl3) δ 10.32 (bs, 1H), 8.33 (d, 1H, J=5.3 Hz), 7.99 (s, 1H), 6.96 (s, 1H), 6.91 (d, 1H, J=5.3 Hz), 4.78 (s, 2H), 0.98 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1)=[O:3].[OH:28]O>C(O)(=O)C>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:11]1)(=[O:28])=[O:3]
Reactant: CS(=O)c1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccccc1-n1ccc(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
To a solution of 1-[2-(methylsulfinyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (60% purity, 300 mg, 0.80 mmol) in 20 mL of acetic acid was added 30% H2O2 aqueous solution (362 mg, 3.19 mmol), and the mixture was stirred at 40° C. for 18 h. The solvents were removed under reduced pressure, water was added, extracted with AcOEt, washed with water, Na2CO3 aqueous solution and brine, dried over Na2SO4, and then concentrated. The residue was purified by prep.-HPLC to give the title compound (20 mg, 6% yield) as a red solid: 1H NMR (400 MHz, CDCl3): δ 2.89 (3H, s), 6.60 (1H, d, J=8.0 Hz), 6.96 (1H, d, J=2.0 Hz), 7.24-7.35 (4H, m), 7.41-7.43 (2H, m), 7.70-7.77 (3H, m), 7.92 (1H, d, J=8.0 Hz), 8.16-8.18 (1H, m); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >90%, Rt=3.073 min; MS Calcd.: 392; MS Found: 393 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[OH2:22]>OP(O)(O)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C:3]=1[C:20]([NH2:21])=[O:22]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O
Agent: O=P(O)(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Yield: 77.5 %

Procedure:
A solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.6 mmol) in H3PO4 (20 mL) was heated to 120° C. for 4 hr. The mixture was then poured into water (100 mL), extracted with EA (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give the product (850 mg, 77.5%) as yellow solid. MS (ESI, m/e) [M+1]+ 295.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[H-].[Na+].[C:30](Cl)(=[O:32])[CH3:31]>CCOCC>[C:30]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 2 h

Procedure:
A solution of 5.6 g. (0.015 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in 450 ml. of warm ether is added dropwise to a slurry of 1.20 g. (0.025 mol.) of 50% sodium hydride in 15 ml. of ether. Upon cessation of gas evolution, 1.42 g. (0.018 mol.) of acetyl chloride is gradually added and the reaction mixture is stirred for two hours at 25°. The mixture is filtered to remove excess sodium hydride and the filtrate is concentrated to give 3-acetyl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, m.p. 111°-112° (hexane).
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[C:6]1([S:3]([CH2:2][C:17]2[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=2[N+:19]([O-:21])=[O:20])(=[O:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of chloromethylphenyl sulfone (10.51 g, 55.13 mmol) in THF (110 mL) was added 5.9 mL (56 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was chilled to 0° C., and 1.0 M potassium tert-butoxide in THF (145 mL, 145 mmol) was added dropwise. The reaction mixture was stirred under nitrogen at ambient temperature for one hour. Acetic acid (9 mL, 160 mmol) was then added. The reaction mixture was solvent evaporated and partitioned in brine and ethyl acetate. The organic phase was then dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was stirred in diethyl ether, filtered and dried in vacuo at 73° C. for 12 hours. 2-Benzenesulfonylmethyl-4-fluoro-1-nitrobenzene as a light brown-yellow solid was obtained (10.24 g, 62.8%): MP: 169-171° C.; Mass spectrum (−EI, [M−H]−) m/z 294. 1HNMR (500 MHz, DMSO-d6): δ8.10-8.14 (m, 1H), 7.70-7.75 (m, 1H), 7.56-7.63 (m, 4H), 7.45-7.50 (m, 1H), 7.20 (dd, 1H, J=9.27 Hz and 2.81 Hz), 5.12 ppm (s, 2H). Elemental Analysis for C13H10FNO4S: Calcd: C, 52.88; H, 3.41; N, 4.74; Found: C, 52.63; H, 3.14; N, 4.66;
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:15]([S:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:23](=[O:25])[CH3:24])(=[O:14])=[O:13])[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: CC(=O)Cl
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12

Procedure:
N-[5-(3,5-Difluorobenzenesulfonylamino)-1H-indazol-3-yl]acetamide can be obtained as described in Example 28 from 0.1 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide, 9 ml of pyridine and 0.024 ml of acetyl chloride. 338 mg of N-[5-(3,5-difluorobenzenesulfonylamino)-1H-indazol-3-yl)-acetamide are thus obtained in the form of a cream solid melting at 268° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: [O-][n+]1nc(CCCN2CCCCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(CCCN2CCCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 86 (1.33 g, 4.2 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 4 h, diluted with dilute aqueous NH3 solution (40 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 87 (1.05 g, 76%) as a red gum: 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.34-3.40 (m, 4H, 2×CH2), 3.27 (t, J=7.1 Hz, 2H, CH2N), 3.12-3.21 (m, 4H, H-6, H-8), 3.05-3.12 (m, 2H, CH2), 2.42-2.51 (m, 2H, CH2), 2.22-2.32 (m, 2H, H-7), 1.64-1.73 (m, 4H, 2×CH2), 1.40-1.51 (m, 2H, CH2); 13C NMR δ 161.8, 155.2, 150.8, 139.1, 134.0, 115.8, 113.9, 58.9, 53.7, 53.4, 33.4, 32.9, 28.0, 25.6, 24.0 (2), 19.7, 13.6; HRMS (FAB+) calcd for C18H25N4O2 (MH+) m/z 329.1974, found 329.1974.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][C:7](=[O:9])[NH:6][C:5]2[N:10]=[CH:11][CH:12]=[CH:13][C:4]1=2.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:6]1[C:7](=[O:9])[CH2:8][O:3][C:4]2[CH:13]=[CH:12][CH:11]=[N:10][C:5]1=2
Reactant: O=C1COc2cccnc2N1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)COc2cccnc21
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.48 g, 12 mmol) is added in portions to a solution of 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (1.50 g, 10 mmol) in DMF (20 mL) at 0° C. and the mixture is stirred for 1 h. 2-(Trimethylsilyl)ethoxymethylchloride (2.1 mL, 12 mmol) is added slowly dropwise and the mixture is then stirred at rt for 1 h. The reaction is quenched by pouring into ice-water and the mixture is then extracted with CH2Cl2 (×3). The combined organic extracts are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][C:21]([NH2:23])=[O:22]>>[C:21]([CH2:20][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])(=[O:22])[NH2:23]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(OCC(N)=O)c([N+](=O)[O-])c1

Procedure:
Reaction of 1.41 g of 4-methoxy-2-nitrophenol, 3.04 g potassium carbonate and 3.61 g of iodoacetamide analogously to the process described in Example 55) gives 2-carbamoylmethoxy-5-methoxynitrobenzene: mp 190°-1° C.; Rf (O)=0.58; FAB-MS: (M+H)+ =227; anal. calc. for C9H10N2O5 : C47.79%, H4.46%, N12.38%; found C47.90%, H4.48%, N12.58%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].Cl.[CH2:16](C(=N)OCC)[CH3:17]>C(O)(=O)C>[CH3:16][C:17]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCCNc1ccc(C(=O)O)cc1N
Reactant: CCOC(=N)CC
Agent: Cl
Solvent: CC(=O)O
Product: CCCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.5 parts of 3-amino-4-(propylamino)benzoic acid, 2.6 parts of ethyl ethanecarboximidate hydrochloride and 50 parts of acetic acid is stirred first for 20 minutes at room temperature and further for 10 minutes at reflux. The reaction mixture is evaporated. The residue is crystallized from 2-propanol. The product is filtered off, washed with water and 2-propanol and dried, yielding 1.8 parts of 2-methyl-1-propyl-1H-benzimidazole-5-carboxylic acid; mp. >260° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:24][N:12]([CH2:11][C:10]1[CH:25]=[CH:26][CH:27]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[N:7][CH:6]=2)[CH:9]=1)[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(-c2cnc(N3CCC(N4CCOCC4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
tert-butyl (2-{[3-(2-Chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (250 mg) was dissolved in DMF (5 ml), and 4-piperidin-4-ylmorpholine (218 mg) and K2CO3 (265 mg) were added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 5% MeOH/CHCl3) to obtain tert-butyl [2-(methyl{3-[2-(4-morpholin-4-ylpiperidin-1-yl)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (285 mg).