Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([C:17](=[O:20])[CH2:18]Cl)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.O>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:10]2[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:18][C:17]1=[O:20]
Reactant: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 100 g (0.32 mol) of N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline and 110 g (0.82 mol) of aluminum chloride in 400 ml of 1,2-dichlorobenzene is stirred vigorously and heated to 140° for 7.5 hours. The reaction is cooled to room temperature and added to a mixture of 100 ml of 12N HCl and 700 ml of water (cooled to 0–5° in a dry ice/acetone bath). The mixture is extracted twice with 400 ml of methylene chloride and the combined organic layers are washed with 600 ml of 3N HCl. The organic layer is stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO G-60). The solids are filtered through a pad of Celite and the solvents are evaporated under reduced pressure to give a tan solid which is recrystallized from ethanol to give N-(2′-chloro-6′-fluorophenyl)-5-methyloxindole, m.p. 137–140°.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19][CH:18]=1.O.Cl>O1CCCC1.C(O)C>[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:42][CH:43]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
Lithium hydroxide monohydrate (153 mg) was added to a solution of ethyl E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate (682 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoic acid (567 mg, yield 87%) as colorless crystals. m.p. 106-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH:12]1[CH2:13][O:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCC1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
A solution of allyl-carbamic acid benzyl ester (9.6 g, 50 mmol) in DCM (250 mL) was treated with mCPBA (11.55 g, 50 mmol, 75% purity) and the mixture was stirred at rt for 4 h. The pH of the mixture was adjusted to 9 by addition of 1M aq. NaOH. The phases were separated and the org. phase dried over MgSO4 and concentrated. The residue was purified by CC (hex/EA 2:1) to give the desired intermediate (7.4 g, 71% yield) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][CH2:23][C:24](Cl)=O.C(N(CC)CC)C>>[CH3:20][O:21][CH2:22][CH2:23][C:24]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: COCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCn1c(CCOC)nc2cnc3ccccc3c21

Procedure:
The method described in Part A of Example 12 was used to treat ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (9.82 g, 37.9 mmol, prepared in Part A of Example 18) with methoxypropionyl chloride (5.54 g, 45.4 mmol). The reaction with triethylamine (21.1 mL, 151 mmol) was heated at reflux for six hours and then subjected to the work-up procedure to provide 10.3 g of ethyl 3-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanoate.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH3-][C:15]#N.[Na+].CC(O)=O>C(#N)C>[CH3:15][N:7]([CH2:8][C:9]([OH:11])=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=C(O)CNc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of N-phenylglycine (5 g, 33 mmol) and formaldehyde (37% aqueous solution, 20 mL) in acetonitrile (100 mL) was added NaBH3CN (6.8 g) and AcOH (2 mL) and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo, the residue was acidified to pH=3-4 and extracted with CHCl3 several times. The combined organic extracts were dried and concentrated to afford a crude product (5.73 g), which was purified by chromatography on silica gel (EtOAc) to afford the title compound (3.96 g, 73%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.OS(O)(=O)=O.[H][H]>C(O)C.O=[Pt]=O>[CH3:1][N:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: Cn1ccc2ccccc21
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN1CCC2CCCCC21
Temperature: 100 °C
Yield: 87.6 %

Procedure:
To a solution of 100 g of 1-methylindole in absolute ethanol in a 600 mL autoclave, 5 g of PtO2 and 10 mL of H2SO4 were added. The mixture was sealed and pressurized with hydrogen to 1500 psig. The reaction mixture was heated at 100° C. overnight while stirring at about 400 rpm. The reaction mixture was pressurized again to 1500 psig and heated at 100° C. for several more hours. The reaction mixture was cooled and filtered to remove the catalyst. The filtrate was concentrated on a rotary evaporator to remove ethanol. The residue was neutralized with sodium hydroxide solution and left to stir at room temperature for about 30 minutes. The solution was transferred to a reparatory funnel and extracted with diethyl ether. The ether layer was dried over anhydrous MgSO4, filtered and concentrated at reduced pressure on a rotary evaporator to give 93.0 g of the product, 1-methyl-octahydroindole, as a yellow oil. The product was confirmed by NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH:11]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[CH2:12][CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>ClCCl.C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH:11]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:18][CH:19]=1)[CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(CC)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)O)C(CC)c1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 16 h
Yield: 82.3 %

Procedure:
2-[1-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-propyl]-malonic acid diethyl ester (3.23 g, 8.19 mmol) was dissolved in a mixture of dichloromethane (12 mL) and ethanol (24 mL, 99.5%). To this solution was added dropwise a solution of potassium hydroxide (0.528 g, 87%, 8.20 mmol) in ethanol (16 mL, 99.5%) at 0° C. over 0.5 h. Stirring was continued for 16 h while the mixture was allowed to warn up to room temperature. After concentration under reduced pressure to 5-10 mL, water (50 mL) was added and the resulting emulsion was stirred for 0.5 h, and then filtered. The filtrate was washed twice with a mixture of ethyl acetate and diethyl ether (2:1, vol/vol). The aqueous layer was acidified by addition of a solution of citric acid in water (10%) to reach a pH of 4 to 5, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, and the solvent was removed under reduced pressure to yield 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propyl]-malonic acid monoethyl ester (2.47 g, 82%)
Reaction SMILES: N[C:2]1C=C([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)C=C[C:7]=1N.[C:17](O)(=O)/[CH:18]=C/C=C/C(O)=O>>[CH:2]#[CH:7].[CH:17]#[CH:18].[N:13]1[C:12]2[CH:14]=[CH:15][CH:9]=[CH:10][C:11]=2[NH:16][CH:17]=1.[N:13]1[C:12]2[CH:14]=[CH:15][CH:9]=[CH:10][C:11]=2[NH:16][CH:17]=1
Reactant: O=C(O)/C=C/C=C/C(=O)O
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: C#C
Product: c1ccc2[nH]cnc2c1

Procedure:
3,3'-Diaminobenzidine (1.508 g, 7.04 mmol) was dehydrochlorinated with 83.3 wt % deaerated PPA in accordance with the procedure enumerated in Example 1. The product of this dehydrochlorination was reacted with trans,trans-muconic acid (1.0 g, 7.04 mmol) in accordance with the procedure of Example 1. This polymerization reaction was conducted for a total of 30 hours, the first 6 hours of which were at a temperature of 100° C. and the final 24 hours at 140° C. The product of this reaction was a yellowish-brown polymerization dope. This product was precipitated in water and purified by extraction, for 3 days, with water.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([CH2:13][O:12][C:9]3[N:8]=[N:7][C:6]([C:4]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)=[O:5])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCSCC2)nn1
Yield: 85 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using thiomorpholine instead of aminomethylcyclopropane, to the title compound (140 mg, 85%) which was obtained as an off-white solid. MS: m/e=415.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[C:14](=O)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:22])[C:14]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C=C(Nc1ccccc1)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Using the procedure of Reynolds and Hauser, Org. Syn. Coll. Vol 3, a mixture of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (1.51 g), benzene (15 ml) and aniline (0.5 g) is azeotropically distilled. The reaction product is purified using a florisil column and eluting with hexane/ethylacetate (9:1) to yield (fractions 2, 3 and 4) ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-phenylamino-2-pentenoate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:22]=[CH:21][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.O>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Sodium azide (210 mg, 1.15 eq) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (901 mg) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into water, and extracted with diethyl ether (3X). The organic phase was washed with water (3X), dried (MgSO4), and evaporated to dryness. Chromatography on silica gel, eluting with hexane/ethyl acetate, gave 4-(4-azidomethylbenzyl)-nitrobenzene (492 mg, 62%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[N:5]([C:10]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])=[O:15])=[C:11]([CH3:13])[N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][O:33][CH2:34][CH2:35]Br>O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:10]2[N:5]3[N:6]=[C:7]([Cl:9])[CH:8]=[C:3]([CH2:2][N:1]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:4]3=[N:12][C:11]=2[CH3:13])=[O:15])=[C:17]([F:23])[CH:18]=1
Reactant: BrCCOCCBr
Reactant: Cc1nc2c(CN)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Temperature: 120 °C
Yield: 31 %

Procedure:
Combine (8-(aminomethyl)-6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-chloro-2-fluorophenyl)methanone (1.15 g, 3.3 mmol), water (12 mL), potassium carbonate (495 mg, 1.1 equiv.), and 2-bromoethyl ether (0.47 mL, 1.1 equiv) in a 20 mL microwave reaction vessel. Seal with a crimp cap then heat in a microwave reactor at 120° C. for 20 min. Cool to RT and partition between EA and water. Wash EA layer with aqueous saturated sodium chloride, and dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo. Purify on silica gel (4:1 hexane:EA→2:1 hexane:EA→1:1 hexane:EA) to give the title compound (0.43 g, 31%) as a light yellow foam. LCMS (4 min)=423.0, 425.0, M+1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:8]=[CH:9][CH2:10][Cl:11].BrCCCCl>C1(C)C=CC=CC=1>[Cl:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCC=CBr
Reactant: C1COCCN1
Agent: ClCCCBr
Solvent: Cc1ccccc1
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
A mixture of morpholine (261 ml, 3.00 mol) and 1-bromo-3-chloropropene (148 ml, 1.50 mol) in toluene (900 ml) was stirred for 18 hours at ambient temperature. Additional 1-bromo-3-chloropropane (25 ml, 0.25 mol) was added, the reaction was stirred for a further 1 hour and then filtered to remove the precipitated solid before the filtrate was concentrated in vacuo. Distillation of the crude oil yielded N-(3-chloropropyl)-morpholine (119.3 g, 49% yield) as the fraction boiling at 70-80° C./2.6 mmHg:
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](O)=[O:17])=[O:10])=[O:6])([CH3:3])[CH3:2].[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CC(O)=O>[CH:1]([O:4][C:5](=[O:6])[NH:7][C@H:8]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:17])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2)=[O:10])([CH3:3])[CH3:2]
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
A mixture of 1-[(R)-isopropoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid (0.20 g), 6-aminomethyl-isoquinolin-1-ylamine (0.6 mmol), N-methyl morpholine (0.2 mL) and 0.19 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 3 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. 0.120 mL CH3COOH were added, the mixture was concentrated and the remaining residue was purified by HPLC (RP-18; H2O/CH3OH 95/5→0/100) to give 0.10 g (35%) of the title compound as a colorless oil. (+)-APCI-MS: 490 (MH+).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[Cl:25])[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.[C:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]>[Pd]>[CH2:12]([C:11]1[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[S:35](=[O:37])(=[O:36])[NH:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[CH:3][C:4]=2[F:29])[C:8](=[O:26])[N:9]([C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[Cl:25])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: [Pd]
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 52 %

Procedure:
The palladium(0)-catalyzed coupling of 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with 2-(N-t-butylsulfamoyl)phenylboronic acid was carried out according to the procedure of Example 28, Step F. Purification of the crude product by flash chromatography on silica gel (gradient elution with 6:1 to 4:1 hexane-EtOAc) provided a 52% yield of the title compound as a stiff, pale yellow foam, mp 124°-126° C.; homogeneous by TLC in 4:1 hexane-EtOAc); mass spectrum (FAB) m/e 616 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:19]OC[Cl:22].[OH-].[Na+]>C(O)(=O)C>[ClH:22].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH2:19][N:11]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9]2
Reactant: COCCl
Reactant: COc1cccc(CCNNc2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(Nc1ccncc1)C2
Product: Cl
Temperature: 0 °C
Yield: 30.4 %

Procedure:
Lithium aluminum hydride (0.55 g) was added portionwise to a suspension of N-[2-(3-methoxyphenyl)ethylidene]-N'-pyridin-4-yl hydrazone (2.0 g) in tetrahydrofuran (36 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hr, sodium sulfate decahydrate was added. The mixture was filtered, and the filtrate was concentrated to give 1.73 g of N-[2-(3-methoxyphenyl)ethyl]-N'-pyridin-4-yl hydrazine. A solution of N-[2-(3-methoxyphenyl)ethyl]-N'-pyridin-4-yl hydrazine (0.85 g) and chloromethyl methyl ether (0.31 g) in acetic acid (15 ml) was heated at 55° C. for 1.5 hrs, and the mixture was cooled to 0° C. Sodium hydroxide solution (15%) was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in methanol and methanolic hydrogen chloride and then ether were added to give 0.31 g (30%) of product, mp 199-200° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:35]2[C:36]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:37][CH:38]=[CH:39][C:34]=2[CH3:33]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3I)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 619.6 (M+H)+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[CH:8]=1)=[O:6].O>CO>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@@H:10]1[C:9]2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)=[O:26]
Reactant: COC(=O)c1ccc2c(c1)[C@@H](NC(=O)c1ccccc1Cl)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@@H](NC(=O)c1ccccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
LiOH (6 equiv.) was added to a suspension of (8S)-8-[(2-chloro-benzoyl)amino]-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (B-07) in methanol and water and the reaction mixture was stirred at 25° C. for 4 hours. (According to TLC control: educt still present). The reaction mixture was topped up with 1 equiv. of LiOH and stirred at 25° C. for 1 hour. Methanol was distilled off and the aqueous residue was diluted with ether and dist. water. The phases were separated and the aqueous phase was acidified with 1N HCl. Finally, the aqueous phase was extracted 4× with ethyl acetate (spot test) and the extract was dried over sodium sulfate and concentrated. Yield: 84.8%
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])=[O:3]
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(C(=O)CBr)c1
Temperature: 80 °C

Procedure:
The compound obtained in Step A (32.2 mmol) is dissolved in glacial acetic acid (40 ml) and then 48.3 mmol of bromine are added. The mixture is heated at 80° C. for 2 hours and is then hydrolysed using ice-cold water. The precipitate obtained is filtered off, washed with water until a pH of 5–6 is obtained, and then dried and recrystallised.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][CH:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:18]([CH:16]([CH3:17])[CH3:15])(=[O:20])=[O:19])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 150 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 530 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 20 minutes and then 2-propylsulfonylchloride (1.5 ml) was introduced dropwise via syringe. After 5 minutes the reaction mixture became homogeneous and was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with 300 ml of ethyl acetate and was washed with brine. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (chloroform-methanol, 95:5 v/v) to yield 0.6 g of the title compound in pure form.