Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13](S(C)(=O)=O)=[N:12][CH:11]=1)[CH3:9])=[O:6].[CH2:23]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33])(=[O:27])=[O:26])[CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:33][C:32]2[CH:34]=[C:28]([S:25]([CH2:23][CH3:24])(=[O:26])=[O:27])[CH:29]=[CH:30][C:31]=2[O:35][CH3:36])=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(S(C)(=O)=O)nn1
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Reaction time: 24 h
Yield: 34.1 %

Procedure:
To a stirred solution of 3-bromo-N-{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 6) (240 mg, 0.62 mmol) in tetrahydrofuran (10 mL) was added 5-(ethylsulfonyl)-2-methoxyaniline (270 mg, 1.2 mmol) and 4-toluenesulfonic acid monohydrate (20 mg). After stirring for 24 hours, silica gel (2.5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (80:20) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-[1-(3-{[5-(ethylsulfonyl)-2-methoxyphenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (110 mg) as a white solid. 1H NMR (CDCl3): δ9.00 (d, J=2.2 Hz, 1H), 8.44 (s, 1H), 8.03 (s, 1H), 7.95 (dd, J=1.9, 1.4 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.57-7.52 (m, 1H), 7.22 (dd, J=8.1, 7.7 Hz, 1H) 7.00 (d, J=8.8 Hz, 1H) 5.44 (dq, J=7.2, 7.0 Hz, 1H), 3.98 (s, 3H), 3.10 (q, J=7.3 Hz, 2H), 1.68 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H). MS m/z 520, 522 (M+1, M+3).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7]1=[O:12].C([N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1)(=O)C.CO>C(#N)C>[CH3:11][N:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][N:18]2[C:19]([CH3:21])=[CH:20][N:16]=[CH:17]2)[C:7]1=[O:12]
Reactant: Cn1ccn(CC#CCBr)c1=O
Reactant: CC(=O)n1cnc(C)c1
Solvent: CC#N
Solvent: CO
Product: Cc1cncn1CC#CCn1ccn(C)c1=O
Temperature: 85 °C
Yield: 79.6 %

Procedure:
A mixture of 1-(4-bromo-2-butynyl)-1,3-dihydro-3-methyl-2H-imidazol-2-one (4.12 g, 0.018 mol) and 1-acetyl-4-methylimidazole (4.47 g, 0.036 mol) in acetonitrile (6 mL) was heated in an oil bath (bath temperature 85° C.) for 1 hr. Methanol (20 mL) was added and, after 1 hr, the solvents were removed and the residue was partitioned between ethyl acetate and 4N NaOH solution. The ethyl acetate was removed and the residual oil was chromatographed on silica gel using methanol:chloroform as eluant to give 3.3 g of product.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[CH:43]=[N:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[N:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cnc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-quinoxaline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].C(=O)([O-])[O-].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)c2ccc(-n3ccnc3)cc2)n2c1ccc1ccccc12
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A mixture of 3-cyano-(4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline (8 mg, 0.025 mmol), pottasium carbonate (10 mg, 0.072 mmol) and imidazole (5 mg, 0.073 mmol) were heated in 500 μL of DMF overnight. The reaction mixture was cooled to room temperature, diluted with 10 mL of ethyl acetate, washed with water (3×10 mL), saturated NaCl and the organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude was purified by chromatography (3% methanol/chloroform) to yield the title compound (6.9 mg, 75%). 1H NMR (CDCl3): 8.21 (dt, J=7.80, 1.20 Hz, 2H), 8.08 (d, J=8.72 Hz, 1H), 8.02 (s, 1H), 7.87 (dd, J=7.81, 1.82 Hz, 1H), 7.73 (m, 2H), 7.60 (m, 4H), 7.46 (s, 1H), 7.42 (t, J=1.24 Hz, 1H), 7.30 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27]1([CH2:33][CH:34]([OH:36])[CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:36][CH:34]([CH3:35])[CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:4][CH:3]=1
Reactant: CC(O)CN1CCCCC1
Reactant: Ic1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(CN1CCCCC1)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.54 g (7.00 mmol) iodobenzene and 2.75 g (10.5 mmol) triphenylphosphane are added successively to a solution of 1.00 g (6.98 mmol) 1-piperidin-1-yl-propan-2-ol in 20 mL DCM. 2.19 mL (10.5 mmol, 95%) diisopropyl azodicarboxylate is added dropwise at RT and the reaction is stirred for 2 h at RT. It is diluted with water, the organic phase is washed with water and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM/MeOH 9:1). The oily residue is triturated with diisopropylether, filtered off from the insoluble residue and the filtrate is evaporated to dryness i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([CH:17]3[CH2:19][CH2:18]3)[C:13]=2[C:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([CH:17]3[CH2:18][CH2:19]3)[C:13]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)cc2)c2c(C)nn(C3CC3)c2C(=O)[O-])cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CNC(c2ccc(Cl)cc2)c2c(C)nn(C3CC3)c2C(=O)O)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
In a 100-mL flask was introduced 4-((4-chlorophenyl)((4-methoxybenzyl)amino)methyl)-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate (Step 23.6) (2.22 g, 4.89 mmol) and LiOH.H2O (0.616 g, 14.67 mmol) in dioxane (15 mL) and H2O (6 mL). The reaction mixture was stirred for hr at rt, quenched with 0.5N HCl (100 mL), and diluted with EtOAc (100 mL). The resulting suspension was filtered to afford the title compound (2.30 g, 4.59 mmol, 94% yield) as a colorless solid. tR: 3.86 min (HPLC 1); tR: 0.87 min (LC-MS 2); ESI-MS: 426 [M+H]+ (LC-MS 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>C1COCC1>[Cl:22][C:9]1[N:10]2[C:14](=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: Fc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Fc1ccc(-c2c(-c3ccccc3)c3n(c2Cl)CCC3)cc1
Reaction time: 0.17 h

Procedure:
The clear solution of 6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 8 d, 2.77 g, 10 mmol) in THF (20 ml) is treated at RT with N-chlorosuccinimide (NCS, 1.34 g, 10 mmol). The solution, immediately turning from yellow to black-coloured with spontaneous heating, is stirred for a further 10 min, then adsorbed on an Al2O3 column (100 g, TSC-ICI), and the substance sought is eluted with ethyl acetate-n-hexane 1:9 (Rf=0.8, starting material Rf=0.6). The eluate fractions are concentrated in vacuo and the residue is crystallized from diisopropyl ether: 1.63 g (52%)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C.O1CCCC1>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (10.13 g) and ethanolamine (3.52 ml) in a mixture of ethanol (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 2 hours. Ethanolamine (3.35 ml) was added and the mixture was stirred at 50° C. for 1 hour. Then, ethanolamine (3.35 ml) was added, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the obtained solid was washed with isopropanoyl, collected by filtration, and dried under reduced pressure to give the title compound (7.25 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:21][CH:20]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)cn2)C1
Temperature: 140 °C

Procedure:
1.0 g (4.99 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 1.383 g (9.99 mmol) of 6-chloropyridine-3-carbonitrile and 1.29 g (9.99 mmol) of diisopropylethylamine were suspended in 40 ml of DMSO and heated in a microwave reactor at 140° C. for 45 min. Most of the DMSO was removed from the mixture by kugelrohr distillation, water was added and the resulting precipitate was filtered off. Drying under high vacuum gave 2.24 g (46% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][C@H:15]1[O:20][C@:16]1([CH3:19])[CH2:17][OH:18].[H][H]>CO.O.[Ni]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(C[C@H]2O[C@]2(C)CO)c1C
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Yield: 86.4 %

Procedure:
185 mg of (2R,3R)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2,3-epoxy-2-methylbutanol are dissolved in 5 ml of methanol and the solution is subsequently diluted with 5 ml of water. Thereupon, Raney-nickel is added and the mixture is heated at reflux under hydrogen for 2 hours. After the hydrogen uptake has finished the mixture is filtered, the filter residue is washed with methanol and methylene chloride and the combined filtrate and washings are concentrated on a rotary evaporator. Residual water is distilled off azeotropically by the addition of methylene chloride. The oil obtained is recrystallized from n-hexane/diethyl ether and there are obtained 161 mg of 55% (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol (48% yield; GC analysis of the acetonide). Data of the pure substance: M.p. 86°-87° C.; [α]D20 +2.55° (c=5.3% in CHCl3).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[I:10][C:11]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([I:21])[C:12]=1N>C(O)(=O)C.C(O)C>[I:10][C:11]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([I:21])[CH:12]=1
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)cc(I)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
13.8 G (0.2M) of solid sodium nitrite were slowly added to stirred concentrated sulfuric acid at 0° C. The resulting thick mixture was stirred at 0° C. for 10 mins. A suspension of 68.28 G (0.175M) of finely powdered 2,6-diiodo-4-nitroaniline in 175 mL of glacial acetic acid was added portionwise cautiously to the above mixture at 0° C. over a period of 25 minutes. This mixture was then stirred 30 mins, and then added to a vigorously stirred suspension of 4 G of cuprous oxide in 420 mL of absolute ethanol over a period of 25 minutes. Vigorous effervescence was observed during this addition. The resulting mixture was stirred 20 mins. at room temperature and then heated to reflux for 30 mins. After cooling, this reaction mixture was poured into large amount of ice. Solid separated was filtered, and washed with water. This solid was dissolved in minimum amount of chloroform, and dried over anhydrous magnesium sulfate. Solvent removal gave 62 G of 3,5-diiodo-nitrobenzene as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.Cl>[CH3:30][O:29][N:28]([CH3:27])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNOC
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (15.8 g, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 g, 114 mmol), DIEA (41 mL, 228 mmol), and BOP (69 g, 156 mmol), were suspended in 80 mL DMF and stirred at room temperature over night. The reaction mixture was diluted with 1 (M) HCl (100 mL), extracted with EtOAc, and the organic portions were washed with 1 (M) aqueous HCl, NaHCO3 and brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide: MS m/z: (M+H) 458.0.
Reaction SMILES: CN1CCCCC1.ClC(OCC(C)C)=O.[CH:16]([O:19][C:20]([NH:22][C:23](=[CH:27][CH3:28])[C:24]([OH:26])=O)=[O:21])([CH3:18])[CH3:17].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>ClCCl>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([NH:39][C:24](=[O:26])[C:23]([NH:22][C:20]([O:19][CH:16]([CH3:17])[CH3:18])=[O:21])=[CH:27][CH3:28])[CH3:38])=[CH:33][CH:32]=1
Reactant: CC=C(NC(=O)OC(C)C)C(=O)O
Reactant: COc1ccc(C(C)N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC=C(NC(=O)OC(C)C)C(=O)NC(C)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
At -20° C., 0.5 g (0.005 mol) of N-methylpiperidine and then, dropwise with stirring at -20° C., 0.7 g (0.005 mol) of isobutyl chloroformate are added to 1.0 g (0.005 mol) of 2-(i-propoxycarbonylamino)-but-2-enoic acid in 10 ml of dichloromethane. After the addition is complete, stirring is continued at -20° C. for a further 10 minutes, and 0.75 g (0.005 mol) of 1-(4-methoxyphenyl)-ethylamine are added, the temperature being kept below -15° C. Stirring is then continued for a further 2 hours at -15° C. and for 15 hours at room temperature, the precipitated solid is filtered off and washed with dichloromethane, the filtrate is concentrated under reduced pressure, the residue is taken up in water and extracted repeatedly with ethyl acetate, the combined organic phases are washed with aqueous sodium bicarbonate solution and water and dried over sodium sulphate, and the solvent is removed under reduced pressure. 0.8 g (47% of theory) of N-[1-(4-methoxyphenyl)-ethyl]-2-(i-propoxycarbonylamino)-but-2-enoic acid amide are obtained as a colourless oil. 1H-NMR (CDCl3, TMS), δ (ppm): 1.25 (m, 6H), 1.50 (d, 3H); 1.74 (d, 3H); 3.79 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:45][C:42]1[CH:41]=[CH:40][C:39]([C:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[C:33]2[CH2:38][CH2:37][N:36]([C:21](=[O:22])[CH2:20][N:3]3[CH2:4][CH2:5][CH2:6][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[O:1])[CH2:35][CH2:34]2)=[CH:44][CH:43]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E) (0.144 g, 0.47 mmol) and 4-(bis(4-fluorophenyl)methylene)piperidine hydrochloride (European Journal of Medicinal Chemistry; 22, 1987; 243-250) (0.15 g, 0.47 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.177 g, 0.47 mmol) and diisopropylethylamine (0.4 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography, eluting with 5% methanol/dichloromethane. 1H NMR (300 MHz, CDCl3) δ ppm 7.17-7.33 (m, 10H), 6.96-7.05 (m, 8H), 4.24 (s, 2H), 3.66 (t, J=5.5 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.42-3.48 (m, 2H), 2.62-2.67 (m, 2H), 2.29-2.42 (m, 4H), 1.75-1.89 (m, 2H); MS (ESI+) m/z 577 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24][O:25][CH2:26][CH2:27]Br.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=1)[CH2:27][CH2:26][O:25][CH3:24])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: COCCBr
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(N(CCOC)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 165 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of ethyl 4-(tert-butoxycarbonyl-amino)cinnamate (1.00 g) in N,N-dimethylformamide (5 ml) in ice water bath under nitrogen and stirred for 1 hour under same condition. To the mixture was added 2-bromoethyl methyl ether (602 mg) and stirred for 1 hour at same condition and at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting to a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 4-[N-tert-butoxycarbonyl-N-(2-methoxyethyl)amino]cinnamate (935 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.044 g, 0.11 mmol) and EtOH (4.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 6%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.020 g, 33%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.78 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H) and 3.53 (s, 2H) (C6H4CH2N and NCH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 7.24 (d, J=3.5 Hz, 1H, thiazole-H), 7.48 (m, 3H, 3,5-C6H4— and thiazole-H), 8.12 (d, J=9.7 Hz, 2H, 2,6-C6H4—), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [OH2:1].[OH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([OH:19])(=[O:1])=[O:18].[OH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: O
Agent: O=c1[nH]c2ccccc2n1CCCO
Solvent: c1ccncc1
Product: CS(=O)(=O)O

Procedure:
To a solution of 52.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one hydrate in 200 parts of pyridine is added dropwise 63 parts of methanesulfonyl chloride. The mixture is stirred and cooled on the air for 2 hours. The pyridine is evaporated. To the residue is added 500 parts of water and the formed precipitate is filtered off. It is dissolved in 350 parts of trichloromethane. This solution is dried over magnesium sulfate and evaporated. The residue is crystallized from 40 parts of methylbenzene, yielding 25.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate; mp. 118°-120° C.