Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:20])=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1
Reactant: COc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reaction time: 0.17 h

Procedure:
To a solution of 5.465 g (20 mmol) 2-(2-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 60 ml dry THF were added at <−60° C. 11.0 ml (22 mmol) lithium diisopropylamide solution 2M in THF/heptanes/ethylbenzene and the mixture stirred for 1.5 h at <−60° C. To the resulting dark brown solution were added 2.5 ml (40 mmol) iodomethane drop wise over 10 min (exothermal, Ti<−48° C.). The resulting light brown solution was stirred at <−50° C. for 2.5 h then quenched with sat. aq. NH4Cl solution and extracted three times with tert-butyl methyl ether. The combined organic phases were washed 3× with brine, dried over Na2SO4, filtered and evaporated: 7.002 g yellow solid: which was purified by flash-chromatography on silica gel with heptane and 5 to 10% AcOEt over 25 min and heptane/AcOEt 90:10 for 20 min. 2-(2-Methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was obtained as light yellow oil: MS (ISP): 288.12 ((M+H)+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](OS(C(F)(F)F)(=O)=O)[C:14]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([NH:41][CH2:42][C:43]#[CH:44])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:44]#[C:43][CH2:42][NH:41][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:14]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1C#CCNC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 29.5 %

Procedure:
Methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(trifluoromethanesulphonyloxy)-benzoate (Intermediate 123, 0.756 g), N-Boc-propargylamine (0.698 g), copper (I) iodide (0.014 g) and bis(triphenylphosphine)palladium(II)chloride (0.026 g) were added to a solution of triethylamine (0.152 g) in acetonitrile (10 ml) and the mixture was heated at 70° C., under nitrogen, for 17 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and DCM with a gradient of 0-10%. After evaporation of the appropriate fractions, the resulting residue was triturated with diethyl ether and the solid was collected by filtration to give methyl 6-(benzenesulphonylmethyl)-2-(3-t-butyoxycarbonylaminoprop-1-yn-1-yl)-3-(furan-3-yl)benzoate (0.225 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C@@H:6]1[C@@H:25]([O:26][CH2:27][CH3:28])[CH2:24][C@@:23]2([CH3:29])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:30])[CH2:20][C@@:19]2([CH3:31])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1)=[O:4].[I-:32].[Na+]>CC(C)=O>[CH2:27]([O:26][C@H:25]1[CH2:24][C@@:23]2([CH3:29])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:30])[CH2:20][C@@:19]2([CH3:31])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7][C@@H:6]1[O:5][C:3](=[O:4])[CH2:2][I:32])[CH3:28]
Reactant: [I-]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(=O)CI
Yield: 85.1 %

Procedure:
3α-Chloroacetoxy-2β-ethoxy-5α-pregnane- 11,20-dione (450 mg) was dissolved in acetone (50 ml) and sodium iodide (460 mg) added to the solution. The mixture was refluxed for one-half hour, a white precipitate forming. The precipitate was filtered off and the filtrate evaporated to a yellow foam which ws partitioned between ether and water. The ethereal solution was dried over anhydrous sodium sulphate and evaporated to give 2β-ethoxy-3α-iodoacetoxy-5α-pregnane-11,20 -dione (460 mg) as a pale yellow foam.
Reaction SMILES: COC1C=CC(CN2CCN(CC3N=CC([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=CC=3)CC2)=CC=1.N[C:49]1[N:54]=[CH:53][C:52]([CH2:55][N:56]([CH3:62])[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[CH:51][CH:50]=1>C(Cl)Cl.CO>[CH3:60][N:59]([CH3:61])[CH2:58][CH2:57][N:56]([CH2:55][C:52]1[CH:51]=[CH:50][C:49]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:34]3[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=3[Cl:45])=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:23])=[N:54][CH:53]=1)[CH3:62]
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]+; TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCCC1>[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:27]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)c(F)c3F)c2)CC1
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) was allowed to stand for 10 min. 2,3,4,5-Tetrafluorobenzoyl chloride (31 μL, 0.229 mmol) was added to the reaction mixture. The reaction mixture was mixed for 24 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with 7M ammonia in methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. This purification was unsuccessful. The solvent was concentrated in vacuo. The residue was dissolved in water, basified with ammonium hydroxide, and extracted with methylene chloride. The organic extracts were washed with brine, glacial acetic acid (0.5 mL) was added to the organic extracts and the solution was mixed for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43.7 mg (97%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-:29].[Na+].OO>C(O)C>[O:29]1[C@H:19]2[C:18](=[O:28])[CH:17]=[C:16]3[C@:21]([CH3:22])([C@@H:20]12)[C@@H:23]1[C@H:13]([C@H:12]2[C@:26]([CH3:27])([CH2:25][CH2:24]1)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]2)[CH:14]=[CH:15]3
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
The trienone from (a) (1 gm) in ethanol (50 mls) at 0° was treated with 10% aqueous sodium hydroxide (0.25 ml) and 30% aqueous H2O2 (2.5 ml). The mixture was stored at 5° overnight and then the resulting epoxide was filtered off, washed with aqueous alcohol and dried to afford the title compound (0.86 mgs). Recrystallization from ethanol gave colourless needles, melting point 107°-109°.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>C1COCC1.O>[Cl:6][C:7]1[C:8]([Cl:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)O1
Reactant: Clc1ccccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
In a 100 ml three necked RB flask equipped with a nitrogen gas inlet and an additional funnel, was taken 4 ml of n-butyl lithium (4 ml, 1.8 M in hexanes). Then 10 ml of dry THF was added and the reaction mixture was kept in −80° C. for 0.5 h. A solution of orthodichlorobenzene (0.01 mol, 1.47 g) in 10 ml THF was added in drops by the additional funnel to the n-butyl lithium solution for the period of 10 minutes with keeping the temperature below −78° C. The mixture was stirred for half an hour to form a pale yellow color. Then a solution of succinic anhydride 1 g (0.01 mol) in 10 ml THF was added slowly for the period of 15 minutes. As the addition continued the reaction mixture turned to yellow color. After one hour water 20 ml was added to quench the reaction and acidified with 5 N HCl. It was then extracted with DCM. The organic layer was dried and evaporated to give the required product as oil which was recrystallized from toluene. LCMS analysis revealed the formation of the product. m/e: 246.98
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[N:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14](Cl)(=[N:21][OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:15]1([C:14]2[N:12]([NH2:13])[C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[O:22][N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NN=C1CCCC1
Reactant: ON=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: NN1C(c2ccccc2)=NOC12CCCC2
Temperature: 25 °C
Yield: 50341.3 %

Procedure:
A round bottom flask was charged with a solution of 20 g of K2CO3 in 50 mL of water and cooled in an ice bath. Cyclopentylidene-hydrazine (7.9 g, 80 mmol) in 25 mL of CH2Cl2 was added, followed by a drop-wise addition of benzohydroximoyl chloride (5 g, 0.032 mmol) in 25 mL of CH2Cl2 over a period of 15 minutes. The mixture was stirred for several days, and allowed to warm to room temperature. Water (50 mL) and CH2Cl2 (50 mL) were added and the phases were separated. The organic layer was washed twice with 50 mL of water, dried over MgSO4, and filtered. The solvent was removed in vacuo, leaving 9 g of a waxy solid. Crystallization from ethyl acetate/hexane provided 3.5 g (50%) of 3-phenyl-1-oxa-2,4-diaza-spiro[4.4]non-2-en4-ylamine after drying. 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.72 ((m, 2H), 7.46 (m, 3H), 3.54 (s, 2H), 2.1 (m, 2H), 1.85 (m, 2H), 1.8 (m., 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C)C=O.C(OCC)(=O)C>[Si:29]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 108 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (178 g) in N,N-dimethylformamide (500 ml) were added imidazole (93.9 g) and t-butyldimethylsilyl chloride (93.9 g), and the mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (2.0 l) and washed in turn with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-4-t-butyldimethylsilyloxy-2-methoxycarbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (260 g).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]1(Br)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([N:21]2[CH2:20][C:19]3[C:23](=[CH:24][C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:15][CH2:14]4)=[CH:17][CH:18]=3)[C:22]2=[O:25])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: BrC1CCCCCC1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1C1CCCCCC1
Yield: 19.5 %

Procedure:
In the same manner as in Example 51, the title compound (12 mg) was prepared from the compound (50 mg) obtained in Example 50 and cycloheptyl bromide (32 mg).
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:20][OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.B(F)(F)F.[CH3:32]COCC>CCOC(C)=O>[Si:1]([O:18][C@H:19]1[CH2:22][CH2:23][CH2:24][O:25][CH2:32][O:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CC(C)(C)[Si](O[C@H](CO)CCCO)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@H]1CCCOCOC1)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To a mixture of 6a (0.55 g, 1.5 mmol) and paraformaldehyde (46 mg, 1.5 mmol) in EtOAc (30 mL), boron trifluoride etherate (195 μL, 1.5 mmol) was added and the resulting mixture was stirred at 23° C. for 4 h. The organic phase was washed with a saturated solution of NaHCO3, dried (Na2SO4) and the solvent was removed. The residue was purified by flash-chromatography (1:4 EtOAc/Hex) to afford 0.29 g (51%) of 7a as a colourless oil: [α]D20=−8.7 (c 1.9, CHCl3); 1H NMR (CDCl3) δ 7.67-7.63 (m, 4H), 7.45-7.34 (m, 6H), 4.69 (d, J=6.2 Hz, 1H), 4.45 (d, J=6.2 Hz, 1H), 4.03-3.95 (m, 1H), 3.70-3.61 (m, 1H), 3.59-3.48 (m, 3H), 1.93-1.80 (m, 1H), 1.77-1.61 (m, 2H), 1.47-1.34 (m, 1H), 1.12 (s, 9H); 13C NMR (CDCl3) δ 135.7, 134.2, 129.5, 127.5, 95.6, 72.2, 71.9, 69.0, 33.2, 27.0, 26.7, 19.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)(=[O:20])=[O:19])[CH2:9][CH2:8]1.O.NN>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Reaction time: 0.5 h

Procedure:
0.06 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2-nitrobenzenesulphonamide is dissolved in 500 ml of MeOH, 2.4 g of 5% Pd-C are added, the mixture is heated to boiling and 0.17 mol of hydrazine hydrate in 50 ml of MeOH is added dropwise within 15 minutes. After boiling for a further 30 minutes, the mixture is filtered, the filtrate is evaporated, the residue is taken up in diethyl ether, washed with water, evaporated again and crystallised from isorpopanol/isopropyl ether.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58](O)=[CH:57][CH:56]=[CH:55][N:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58]([O:14][CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[OH:4])=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: Oc1cccnc1Oc1cccc(Br)c1
Reactant: COCOc1cnccc1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (2.50 g, 12.7 mmol) obtained in Example 2 and triphenylphosphine (4.50 g, 17.0 mmol) are dissolved in THF (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (3.00 g, 15.0 mmol) and 2-(3-bromophenoxy)-3-pyridinol (2.50 g, 9.4 mmol) obtained in Reference Example 11 under ice-cooling. The mixture is further stirred at 40° C. for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 47% aqueous hydrobromic acid solution (20 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, and neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate/ethanol), recrystallized from ethanol/diethyl ether to give the title compound (3.10 g) as colorless crystals, m.p. 116-118° C.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:33])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2ccccc2)SCC(NC(CCc2ccccc2)C(=O)O)C1=O

Procedure:
90 mg of α-{6-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 10 above) was hydrolysed with aqueous sodium hydroxide in the manner described in Example 5, giving the title compound as a powder in a yield of 70 mg.
Reaction SMILES: N(OCCC(C)C)=O.[Cl:9][C:10]1[C:11]([CH3:17])=[C:12]([CH:14]=[CH:15][CH:16]=1)N.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:9][C:10]1[C:11]([CH3:17])=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccccc1
Reactant: Cc1c(N)cccc1Cl
Agent: CC(C)CCON=O
Product: Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry nitrogen atmosphere isoamyl nitrite (37 grams, 0.31 mole) was added to a stirred solution of 3-chloro-2-methylaniline (35 grams, 0.25 mole) in benzene (500 ml). The mixture was heated at reflux for 1.5 hours, then allowed to cool and stirred at 50° for approximately 18 hours. The reaction mixture was cooled to room temperature, then evaporated under reduced pressure to a red residue. The residue was distilled under reduced pressure to give a yellow oil (bp 115°-130°/0.9 mm). The pot residue was washed with chloroform and the distillate dissolved in chloroform. The chloroform fractions were combined, washed with 10% aqueous hydrochloric acid and evaporated to give 3-chloro-2-methyl[1,1'-biphenyl] as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][CH3:23])=[O:13].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:11][C:12]([C:14]1[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:13]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COc1cccc(OC)c1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1C(=O)C=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
(40) To a solution of 2,6-dichlorobenzaldehyde (485 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring for 1.5 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 481 mg (51.5%) of faint-yellow needles: mp 126.8-127.8° C. 1H NMR (250 MHz) δ 7.48-7.42 (d, 1H), 7.37-7.31 (m, 3H), 7.11-6.63-6.60 (d, 2H), 3.81 (s, 6H); 13C NMR (62.7 MHz) 195.1, 158.0, 138.4, 136.5, 135.2, 132.6, 131.4, 130.0, 129.0, 117.9, 104.2, 56.1 ppm. Elemental Analysis. Calculated for C17H14Cl2O3: C, 60.55; H, 4.19. Found: C, 60.60; H, 4.18.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[NH2:32]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[O:27][N:32]=[C:31]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccncc1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccncc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 37.7 mg (0.275 mmol) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 88.7 mg (69% of theory).