Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:10]=3[S:9](=[O:20])(=[O:19])[C:8]=2[CH:21]=1)([O-])=O.CN(C)C=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=3[S:9](=[O:20])(=[O:19])[C:8]=2[CH:21]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1cc([N+](=O)[O-])ccc1-2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Yield: 97.7 %

Procedure:
A mixture of 10.0 g of 3,7-dinitrodibenzothiophene S,S-dioxide, 180 ml of dimethylformamide, 20 ml of glacial acetic acid and 1.0 g of 5% palladium on carbon was hydrogenated in a Parr apparatus until hydrogen uptake ceased. The mixture was then filtered through diatomaceous earth, the filtrate poured into 1 liter of ice water, the solid collected by filtration, washed with ethanol and ether and dried at 110° C., giving 7.86 g of the desired product as a solid mp 320°-330° C.(dec.).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1)[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH2:3]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=1)[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC/C=C\CCCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC/C=C\CCCOc1ccc(C(=O)O)cc1
Yield: 98.1 %

Procedure:
550 μL of 1 N sodium hydroxide solution (550 μmol) are added portionwise to 109 mg of 33 (358 μmol) in methanol (4 mL). The solution is refluxed for 20 hours. After evaporating off the solvent, the reaction medium is acidified with 0.5 N HCl and extracted with DCM. 102 mg of a white solid are obtained, i.e. a yield of 98%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
Methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.120 g) was suspended in DCM (5 mL). Pyridine (0.885 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.180 g) were added. The mixture was stirred at room temperature for 5 hours then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5M aqueous hydrochloric acid solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-10% to give methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.208 g) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Step 1B [Intermediate 2: 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (3.4 g, 9.71 mmol), 4-hydroxymethyl phenyl boronic acid (1.48 g, 9.71 mmol, 1 equiv.), Pd(PPh3)4 (561 mg, 0.48 mmol, 0.05 equiv.) were dissolved in ethylene glycol dimethyl ether (90 mL) under N2 atmosphere and stirred at room temperature for 30 min. Then K2CO3 (2.68 g, 19.4 mmol, 2 equiv.) in H2O (30 mL) was introduced to the reaction mixture and heat to reflux overnight. After TLC confirmation of reaction completion, solvent was removed by rotovap, residue partitioned between EtOAc and brine, organic layer dried over MgSO4, solvent removed, crude residue was triturated with EtOAc to give 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester in 67% yield (2.46 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[Br-:20]>>[Br:20][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11]
Reactant: [Br-]
Reactant: COc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Product: COc1ccc(C(=O)C(Br)Cc2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 3-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlC3 was used as catalyst. The obtained product was a white solid in a yield of 95.0%, mp: 76-77 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.31 (1H, dd, J=14.28, 7.00 Hz), 3.66 (1H, dd, J=14.28, 7.28 Hz), 3.87 (3H, s, OCH3), 5.23 (1H, t, J=7.56 Hz, CHBr), 6.93 (2H, d, J=8.96 Hz, ArH), 6.96 (2H, t, 3JFH=3JHH=8.72 Hz, ArH), 7.23 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 7.95 (2H, d, J=8.96 Hz, ArH); ESI-MS: 339.2 (M+2, 89), 337.0 (M, 70), 257.2 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1>C(O)C.Cl.[Fe]>[NH2:25][C:21]1[CH:20]=[C:19]([CH:3]2[C:2]([CH3:1])([CH3:28])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[CH:9]=3)[NH:4]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a mixture of N-[3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (2 g, 5 mmol) in ethanol 95% (100 mL) and 10% hydrochloric acid (20 mL) was added iron (0.84 g, 15 mmol). The reaction mixture was stirred at 95° C. for 1 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford N-[2-(3-Amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (1.5 g, 80%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C19H23N3O3S (M+H)+: 374.48, observed: 374.1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](O)[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.C(N(CC)CC)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:31](=[O:32])[NH:30][CH3:29])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1
Reactant: O=c1cc(Oc2c(Cl)cccc2Cl)c2cc(O)ccc2o1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,6-dichlorophenoxy)-6-hydroxycoumarin (0.5 g, 1.55 mmole) in dimethyl formamide, under nitrogen, at room temperature is treated with triethylamine (0.7 mL, 5 mole), then treated with CH3NCO (0.5 mL, 5.5 mole) and allowed to stir at room temperature for about 1 hour. When the reaction is complete by HPLC analysis, the reaction mixture is poured onto water and extracted with methylene chloride. The extracts are concentrated in vacuo to give a residue. The residue is crystallized from methylene chloride/hexane to afford the title product as white crystals, 0.382 (71% yield), mp 292°-299° C., identified by 1HNMR, 13CNMR and IR analyses.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH2:28][OH:29].C(N(CC)CC)C>CN(C=O)C>[CH3:22][C:23]1[N:24]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[N:26][C:27]=1[CH2:28][OH:29]
Reactant: Cc1nc[nH]c1CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 50.4 %

Procedure:
A solution of triphenylchloromethane (13.1 g) in dry DMF (80 ml) was added dropwise over 30 min. to a stirred solution of 4-methyl-5-imidazolemethanol hydrochloride (7.0 g) and triethylamine (9.52 g) in dry DMF (75 ml) at room temperature under nitrogen, and stirring was continued for 2.5 h. The suspension was poured onto ice (600 ml), stirred for 30 min. and filtered. The resulting solid (12.0 g) was triturated twice with acetone (2×250 ml) to give the title compound (8.4 g), t.l.c. (System A 94.5:5:0.5) Rf 0.19.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1>C(O)C>[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38]2[N:42]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1
Reactant: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nc(/C=C/c2nc3n(n2)CCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 23.8 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (120 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (6.6 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (6.03 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 150 mg of the racemic title compound. The racemic title compound (150 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (54 mg) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (51 mg).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4]1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH:3]3[CH2:4][CH2:5]3)[CH2:8][CH2:9]2)[N:16]=1
Reactant: OC1CCN(CC2CC2)CC1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(OC2CCN(CC3CC3)CC2)n1
Reaction time: 0.33 h
Yield: 61 %

Procedure:
Add NaH (60% dispersion in oil, 130 mg, 3.25 mmol) to a solution of 1-cyclopropylmethyl-piperidin-4-ol (preparation 11, 458 mg, 2.95 mmol) in DMF (8 mL) and stir for 20 min. Then add 2,6-dichloropyridine to the mixture and heat at 120° C. overnight. Quench the reaction with saturated NaHCO3, extract with methylene dichloride three times. Combine the organic layers, wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 4% 2M NH3-methanol in methylene dichloride provides 480 mg (61%) of the title compound: mass spectrum (ion spray): m/z=267.2 (M+1); 1H NMR (CDCl3, ppm): 7.39 (t, 1H), 6.75 (d, 1H), 6.52 (d, 1H), 4.96 (m, 1H), 2.75 (m, 2H), 2.30 (m, 2H), 2.19 (d, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 0.76 (m, 1H), 0.43 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[NH2:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9]2)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2N)C1
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-Butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate and 3-amino-6-bromopicolinic acid were coupled yielding after column chromatography tert-butyl (3S,5R)-1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate. LC/MS (m/z): 509.1/511.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:10]=[CH:11][C:2]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
A stirred solution of methyl 2-bromo-5-(2-oxopyrrolidin-1-yl)benzoate (D52, 1.7 g; 5.73 mmol) in DMF (13 ml) was treated with 4-boronobenzoic acid (0.95 g,5.73 mmol) under argon, followed by tetrakis(triphenylphosphine)palladium (O) (104 mg) and triethylamine (2.34 ml, 0.02 mol). After heating for 18 h at 100° C., the reaction mixture was concentrated under reduced pressure and the residue partitioned between 10% aqueous Na2CO3 solution and ethyl acetate. The basic aqueous layer was acidified with 5M HCl acid, precipitating the crude product as a white solid, which was recrystallised from ethanol (137 mg, 7%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N:18]1([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: C1CNCCNC1
Product: c1ccc(OCCOc2nccnc2N2CCCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and homopiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 141 mg (75%) of the title product. Anal. (C17H22N4O2.0.35EtOAc) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]([CH3:32])[C:16]([C:18]([NH:21]C(=O)OCC1C=CC=CC=1)([CH3:20])[CH3:19])=[O:17])=O.C(=O)(O)[O-].[Na+]>Br>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]1[C:6]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]([CH3:32])[C:16](=[O:17])[C:18]([CH3:20])([CH3:19])[N:21]=1
Reactant: CN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h

Procedure:
A solution of 20 mg (0.04 mol) of benzyl [1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]-methylcarbamoyl]-1-methylethyl]carbamate in 0.5 ml of hydrogen bromide/glacial acetic acid (30 percent) is left to stand for 15 minutes, subsequently treated with a 10 percent sodium bicarbonate solution and extracted several times with methylene chloride. The organic phase is dried over sodium sulphate and concentrated, whereupon the residue is chromatographed on a pressure column containing 2 g of silica gel (particle size 0.04-0.06 mm) under 0.2-0.4 atmospheres of nitrogen with methylene chloride as the elution agent. By crystallisation from ether/petroleum ether there is obtained 5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 127°-129°.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[N:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:23][CH2:22][CH2:21][N:9]1[C:10]2=[N:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=[C:15]2[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:8]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCOCc1ccccc1
Reactant: N#Cc1ccc2c(C3CCCCC3)c[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(C3CCCCC3)cn(CCOCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a solution of 3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.0 g, 13.7 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (213 mg, 5.33 mmol) under ice-cooling, and the mixture was stirred for 15 min. After stirring, benzyl 2-bromoethyl ether (0.77 ml, 4.88 mmol) was added and the mixture was stirred at 50° C. for 1 hr. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give 1-(2-benzyloxyethyl)-3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (1.44 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].Cl.[CH3:20][NH:21][O:22][CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:16])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CNOC
Reactant: COc1cc(N2CCC(C(=O)O)CC2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(N2CCC(C(=O)N(C)OC)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid (9.0 g, 33.4 mmol), N,O-dimethylhydroxylamine hydrochloride (4.88 g, 50.1 mmol) and DCM (15 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.59 g, 50.1 mmol) and 4-(dimethylamino)pyridine (0.408 g, 3.34 mmol). The mixture was cooled in an ice bath and treated with N,N-diisopropylethylamine (11.62 mL, 66.7 mmol) over 3 min. After 10 min, the cooling bath was removed and the mixture was stirred at RT overnight (ca. 14 h). At the conclusion of this period, the mixture was diluted with DCM (50 mL), and then washed successively with saturated NaHCO3 (3×25 mL), 1 M HCl (2×50 mL) and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography using a 120 g silica gel cartridge and 10:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 1-(4-chloro-3-methoxyphenyl)-N-methoxy-N-methylpiperidine-4-carboxamide as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=1.[C:52]([CH2:54][CH2:55][S:56]([C:59]1[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=1)(=[O:58])=[O:57])#[N:53]>N1C=CC=CC=1>[C:52]([CH2:54][CH2:55][S:56]([C:59]1[CH:64]=[CH:63][C:62]([S:65]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=2)(=[O:66])=[O:67])=[CH:61][CH:60]=1)(=[O:58])=[O:57])#[N:53]
Reactant: N#CCCS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(N)c2ccccc2c1O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2ccc(S(=O)(=O)CCC#N)cc2)c2ccccc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 4-amino-1-hydroxy-N,N-dioctadecyl-2-naphthamide (U.S. Pat. No. 4,135,929) (0.03 mol) in 450 ml of degassed pyridine was cooled to 5° to 10° C. and 8.8 g (0.03 mol) of 4-(2-cyanoethylsulfonyl)benzenesulfonyl chloride was added scoopwise at 0° to 5° C. The mixture was stirred for one hour at this temperature and was warmed to 20° to 25° C. and held for one hour. The reaction mixture was drowned in 2 liters of ice and water, filtered, reslurried in water and dried. The product was recrystallized from hexane to give 18 g (62 percent) of a tan solid, melting point 85° to 86° C.