Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: Brc1ccnnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(-c2ccnnc2)c1
Reaction time: 3 h

Procedure:
([2-(benzyloxy)-5-(trifluoromethyl)phenyl]boronic acid (3.72 g, 0.0126 mol) and caesium carbonate (8.9 g, 0.0273 mol) were suspended in 1,4 dioxane (40.0 mL) and water (20.0 mL). The reaction was degassed twice before being brought to 80° C. under nitrogen. Then 4-bromopyridazine hydrobromide (Preparation see above, 2.52 g, 0.0105 mol) and palladium tetrakistriphenylphosphine (0.62 g, 0.000537 mol) were added to the reaction and it was stirred for three hours. The reaction was concentrated in vacuo to 20.0 mL, and partitioned between ethyl acetate (70.0 mL) and saturated aqueous brine (50.0 mL). The two layers were filtered over arbocel™ to remove a fine black solid. Then the organic layer was washed with more saturated aqueous brine (2×50.0 mL) and it was dried over sodium sulphate. The solvents were concentrated in vacuo and crude was purified using ISCO™ (using a gradient of 0-50% ethyl acetate in heptane, 80 g SiO2) to afford the title compound as a light orange solid.
Reaction SMILES: CO[C:3]([C:5]1[N:23]=[C:8]2[CH2:9][N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[C:16]([N:7]2[N:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4].[CH3:24][NH:25][CH3:26]>CO>[CH3:24][N:25]([CH3:26])[C:3]([C:5]1[N:23]=[C:8]2[CH2:9][N:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[C:16]([N:7]2[N:6]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4]
Reactant: CNC
Reactant: COC(=O)c1nc2n(n1)-c1ccccc1N(c1ccccc1)C2
Solvent: CO
Product: CN(C)C(=O)c1nc2n(n1)-c1ccccc1N(c1ccccc1)C2

Procedure:
A mixture of 7.00 g (0.023 mol) of the 5-phenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxylic acid methyl ester prepared according to Example 1(f) in 300 ml of methanol and 62.6 ml (0.457 mol) of 33% ethanolic dimethylamine solution is heated at 100° in an autoclave for 16 hours. The reaction mixture is then concentrated by evaporation in vacuo and the residue is dissolved in methylene chloride and a mixture of ice and water. The organic phase is washed twice with cold 5% potassium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The amorphous residue crystallises when triturated with 300 ml of ether. After filtration and drying in a high vacuum, there is obtained N,N-dimethyl-5-phenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-2-carboxamide which sinters from 125° and gradually melts at 150°-165°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[O:21])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CC(C)c1cc(CN)on1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-(1-methylethyl)-5-isoxazolemethanamine as starting materials; LC-MS (UV peak area/ESI) 100%, 454.1134 (M+H)+.
Reaction SMILES: Cl[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H-].[CH3:15][Al](C)C.[Na+].C[O-].[Na+].Cl>CCCCC>[CH3:13]/[CH:12]=[CH:11]\[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:15]
Reactant: C[Al](C)C
Reactant: CCCCCCCCCCC#CCl
Agent: C[O-]
Agent: Cl
Agent: [H-]
Solvent: CCCCC
Product: C/C=C\CCCCCCCCCC
Temperature: 50 °C

Procedure:
By a procedure similar to that described in Example 9, 1.00 g (5.00 mmol) of 1-chloro-1-dodecyne was hydroaluminated with sodium trimethylaluminum hydride and then treated with sodium methoxide. After heating the reaction mixture overnight at 50° C., it was slowly poured into a mixture of 3N HCl and pentane. The aqueous layer was extracted with pentane and the combined organic phase was washed sequentially with 3N HCl, saturated NaHCO3, and saturated NaCl. Analysis by GC (using n-nonane as an internal standard) showed the presence of 2% 1-dodecene, 29% 1-dodecyne, and 69% cis-2-tridecene. Short-path distillation provided a pure sample of cis-2-tridecene; bp=49./0.2 torr; IR (neat) 3050 (w), 2960 (m), 2920 (s), 2850 (s), 1660 (w), 1470 (m) cm-1 ; 1H--NMR (CDCl 3, TMS) (ppm) 0.85 (t, 3H), 1.2 -1.4 (br s, 16H), 1.55 (d, J= 6 Hz, 3H), 2.0 (m, 2H), 5.40 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: COc1cccc(S)c1
Product: COc1cccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)c1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3-methoxy-thiophenol.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:1](=[O:12])([S:20][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCS
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-heptanethiol as starting materials to give the aimed compound.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:27].Cl>O1CCOCC1.O>[F:26][C:21]1[CH:20]=[C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:28])=[O:4])=[C:8]2[CH3:27])(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(F)c2)c2ncccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1M Aqueous LiOH (0.52 mL) is added at 0° C. to a stirring solution of [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (200 mg, 0.526 mmol) in 1:1 dioxane/water (4 mL). The reaction mixture is stirred at 0° C. for 15 minutes, then allowed to warm to room temperature. After 2.5 hours, the reaction mixture is neutralised to pH 7 with 1M HCl and the solvent is removed under reduced pressure. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% CH2Cl2 to 5% methanol in CH2Cl2 to afford [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=367.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:26]4[C:35]5[C:30](=[CH:31][C:32](Cl)=[CH:33]C=5)N=CC=4)[CH2:18][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.BrCCCCCCBr.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:25]1([CH2:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:17][CH2:18]2)[CH2:26][CH2:35][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Clc1ccc2c(NCCCN3CCN(CCCNc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Agent: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(NCCCN3CCN(CCCN4CCCCCC4)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,4-bis{3-[N-(7-chloroquinolin-4-yl)amino]propyl}piperazine described in example 1 (0.15 g, 0.41 mmol), 1,6-dibromohexane (0.077 mL, 0.5 mmol) in DMF (5 mL), K2CO3 (287 mg, 2.07 mmol) is added. After stirring the mixture at room temperature for 48 h, the solvent was removed under reduced pressure. The residue was solubilized in CH2Cl2, washed with NaHCO3 1M and dried over MgSO4. Crude compound is purified by thick-layer chromatography (CH2Cl2/MeOH/NH4OH: 80/20/2.7).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([CH:10]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C(CCc1ccccc1)c1ccc(-c2ccccc2)c(F)c1

Procedure:
1.93 g of 60% oily sodium hydride was suspended in 70 ml of dimethylformamide, and a solution of 10.0 g of 2-fluoro-4-biphenylyl acetone in 30 ml of dimethylformamide, was added under cooling with ice with stirring, followed by stirring at room temperature for 50 minutes. Then, 7.20 ml of phenethyl bromide was added, followed by stirring at room temperature for 18 hours. The reaction solution was extracted by an addition of water and ethyl ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 10.9 g of the above identified compound as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-nitro-benzoic acid (1.0 g, 5.0 mmol) in ethanol (10.0 ml) was treated with concentrated sulfuric acid (0.30 ml) and stirred at reflux overnight. On cooling to room temperature and then to 0° C. a crystalline precipitate formed. This was filtered washing with ethanol/water 2:1, and dried under vacuum, yielding 2-fluoro-4-nitro-benzoic acid ethyl ester (0.75 g, 65%) as an off-white crystalline solid.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1.O>C1COCC1>[F:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][OH:4])[CH:12]=[CH:11][C:10]=1[C:13]#[N:14]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCO)cc1F
Reaction time: 12 h

Procedure:
LiBH4 (1.94 mL, 3.88 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-3-fluorophenyl)acetate (0.50 g, 2.59 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (10 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give the product as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.60 (dd, J=7.4, J=7.1 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=7.3, J=9.1 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 2.93 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:30][CH2:31][CH3:32])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:33](Cl)([Cl:35])=[O:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:33]([Cl:35])=[O:34])[C:10]([C:20]3[C:21]([O:30][CH2:31][CH3:32])=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C27H24N6O3F3Cl2 [(M+H)+] 607.1234, observed 607.1231.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2[S:11](=[O:14])(=[O:13])[NH2:12])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: O
Product: CN1CCN(c2ccc(C(N)=O)cc2S(N)(=O)=O)CC1

Procedure:
165 Grams of 4-chloro-3-sulfamoylbenzoic acid-amide (0.7 mole) were stirred with 0.3 l of N-methylpiperazine for 1 hour at 130° C. Subsequently the reaction mixture was diluted with 2 l of water, and the crystalline precipitate was suction-filtered. The crude product (150 g with a degradation point of 301° C.) was dissolved in 3 l of 0.5N HCl and, after the solution had been decolorized with activated charcoal, the said product was precipitated in a crystalline state, at pH 8, by means of 2N ammonia.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCCCCO
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCCCCO

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 4-hydroxybutylamine.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-])=O)[CH:5]=1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:13][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(C(=O)O)c(N)c1
Yield: 98 %

Procedure:
The product of Example 431C (0.697 g, 3.332 mmol) was hydrogenated in methanol (30 mL) with 10% palladium-on-carbon (70 mg) at 1 atmosphere hydrogen pressure (balloon) for 2 hours. The reaction was filtered through a 0.45 micron PTFE membrane and the catalyst thoroughly washed with methanol. The filtrate was concentrated by rotary evaporation to give the title compound (0.585 g, 3.264 mmol, 98%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.15 (d, J=6.62 Hz, 6 H) 2.61-2.92 (m, 1 H) 6.41 (dd, J=8.46, 1.47 Hz, 1 H) 6.58 (d, J=1.84 Hz, 1 H) 7.60 (d, J=8.46 Hz, 1 H) 8.46 (br s, 2 H); MS (ESI+) m/z 180 (M+H)+.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][N:9]([C:15]1[O:16][CH:17]=[C:18]([CH3:20])[N:19]=1)[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])([O:3]CC)=[O:2].[OH-].[Na+]>C(O)C>[C:1]([CH2:6][CH2:7][CH2:8][N:9]([C:15]1[O:16][CH:17]=[C:18]([CH3:20])[N:19]=1)[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCN(C(=O)C(C)C)c1nc(C)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1coc(N(CCCC(=O)O)C(=O)C(C)C)n1
Yield: 57.3 %

Procedure:
A solution of 2[N-(3-carbethoxypropyl)-isobutyramido]-4-methyloxazole (9.9 g., 0.035 mol.) prepared in a manner similar to that described in Example 44 was dissolved in ethanol (100 ml.) and N NaOH solution (35 ml.) and the solution was stirred for 20 hours at ambient temperature. The solution was evaporated and the residue was dissolved in water, washed with ether, acidified and extracted with ether. The extract was dried and evaporated and the residue was recrystallised from benzene-- petrol to give the product 5.1 g., m.p. 81°- 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18](F)[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].BrC1SC(C(OCC)=O)=NC=1C1C=CC(F)=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Agent: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Product: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cccc(Cl)c2)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 4A. 80.0 mg (79% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[O:9]=[C:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C1CNCCN1
Solvent: CC#N
Product: O=C1CN(c2cncc(Cl)n2)CCN1

Procedure:
A mixture of 10.0 g (0.0067 mole) of 2,6-dichloropyrazine and 14 g (0.14 mole) of 2-oxopiperazine in 100 ml of acetonitrile is refluxed 1.5 hour with stirring under N2. The mixture is concentrated under vacuum, the residue titrated with water and filtered, and the crude solid recrystallized from water (charcoal treatment) to give off-white plates of the subject compound, 7.7 g, mp 192°-193° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C@H:18]([CH3:21])[CH2:19][OH:20]>CN(C=O)C>[CH:10]1[C:11]2[N:12]([CH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](CO)CBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CO)Cn1c2ccccc2c2ccccc21
Temperature: 45 °C
Reaction time: 48 h
Yield: 22.3 %

Procedure:
Carbazole (0.50 g, 3.0 mmol) was dissolved in dry DMF (20 mL) and NaH (60% dispersion in oil) (0.36 g, 9.0 mmol) was added. The resulting mixture was stirred under a N2 atmosphere at 25° C. for 30 min. (R)-(-)-3-Bromo-2-methyl-1-propanol (1.14 g, 7.5 mmol) was added in 4 portions over a period of 10 min, and the mixture stirred at 45° C. for 48 h. The solvent was removed in vacuo. Addition of water (20 mL), extraction with CH2Cl2 (3×20 ml), drying of the organic phases (MgSO4) and evaporation of the solvent in vacuo gave an oil that was purified on a silica gel column (Eluent: ethyl acetate/n-heptane (1:1)). This afforded the title compound 0.16 g (23%) as a white solid. M.p. 80-81° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].[F:29][C:30]1[CH:38]=[C:37]([CH3:39])[C:33]([C:34](O)=[O:35])=[C:32]([CH3:40])[N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O>[F:29][C:30]1[CH:38]=[C:37]([CH3:39])[C:33]([C:34]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11]2)[CH3:5])=[O:35])=[C:32]([CH3:40])[N:31]=1
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1cc(F)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(F)nc3C)CC2)cc1
Yield: 68.1 %

Procedure:
To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (41 mg, 0.11 mmol) in DMF (0.5 mL) was added 6-fluoro-2,4-dimethyl-nicotinic acid (27 mg, 0.16 mmol), HOBT (20 mg, 0.15 mmol), EDCI (29 mg, 0.15 mmol) and DIPEA (55 μL, 0.32 mmol). After the mixture was stirred at room temperature overnight brine (5 mL) was added, and the mixture was extracted with CH2Cl2 (2×5 mL). The organic extracts were combined and dried (Na2SO4). After filtration the solvent was removed under vacuum, and the residue was purified by flash chromatography on a silica gel column (50:1:0.1, CH2Cl2/MeOH/NH4OH) to afford the title compound as a white solid (40 mg, 67%). 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.6 Hz), 1.00 (m, 1H), 1.19 (m, 1H), 1.54 (m, 1H), 1.72 (m, 1H), 1.82 (br d, 2H, J=12.6 Hz), 2.12 (t, 1H, J=10.5 Hz), 2.32 (s, 3H), 2.34 (s, 3H), 2.47 (s, 3H), 2.48 (t, 1H, J=12.6 Hz), 2.65-2.85 (m, 3H), 3.15-3.45 (m, 2H), 3.72 (s, 3H), 3.82 (m, 1H), 3.96 (s, 2H), 6.51 (s, 1H), 6.60-6.76 (m, 4H), 7.03 (d, 1H, J=4.8 Hz), 8.08 (br. S, 1H), 8.25 (s, 1H), 8.29 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.81, 19.08, 19.50, 22.26, 30.09, 30.90, 31.82, 39.89, 44.46, 47.79, 52.05, 55.92, 59.16, 59.94, 107.62 (d, 1C, J=146 Hz), 114.75 (2C), 120.21 (2C), 125.48, 132.05, 133.47, 142.68, 145.64, 148.27, 149.45, 150.58 (d, 1C, J=32 Hz), 153.08 (d, 1C, J=48 Hz), 162.64 (d, 1C, J=949 Hz), 162.88, 167.92. ES-MS m/z 533 (M+H). Anal. Calcd. For C31H40N5FO2.0.2CH2Cl2: C, 68.05; H, 7.39; N, 12.72. Found: C, 68.26; H, 7.78; N, 13.08.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl-].[NH+]1C=CC=CC=1.OS(O)(=O)=O>O>[OH:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CCCC(=O)N2
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1CCCc2c(O)cccc2N1
Yield: 45.1 %

Procedure:
3.8 g (0.02 mole) of 6-methoxy-2,3,4,5-tetra-hydro-1H-1-benzazepin-2-one and 10 g of pyridinium chloride are heated for 2 hours at 200°-220° C. The melt is cooled and poured into water, and the mixture is acidified with 2 N H2SO4 and extracted repeatedly with ether. The combined organic phases are dried and concentrated and the residue is recrystallized from an acetone/cyclohexane/ethyl acetate mixture in the presence of animal charcoal. 1.6 g of 6-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, of melting point 243°-244° C., are obtained. This material is identical with the product obtained under Ia.