Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][CH:16]=[O:17])[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:26]3[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[CH:7]([NH:15][CH:16]=[O:17])[CH2:6][CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC=O)CC1C
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: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)C(NC=O)CC(C)N3C(C)=O)cc1
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a suspension of intermediate 3 (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (62.24 g) in DME (600 ml) was added palladium tetrakis (11.56 g) at room temperature. After 10 min of stirring, were added {4-[(methyloxy)carbonyl]phenyl}boronic acid (54 g) and a 2N solution of Na2CO3 (300 mL) and the mixture was stirred heated to reflux for 16 h. The mixture was concentrated under reduced pressure. After addition of 200 ml of DCM to the residue, the product precipitated, it was filtered and washed with water (3*100 mL). To remove the rest of the water, the solid was washed with isopropyl ether (100 ml), the solid was then added to 220 ml of warm isopropyl ether and the resulting mixture was left in the sonicator. The solid was filtered off and dried to afford the title compound as a beige solid (64.7 g)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[F:16][C:17]1[CH:18]=[C:19]([C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]5[CH:48]=[CH:47][N:46]=[C:45](S(C)(=O)=O)[N:44]=5)[N:38]=4)=[CH:35][N:36]=3)[N:33]=2)[CH:20]=[CH:21][CH:22]=1>CS(C)=O.C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:34]([C:37]4[N:38]=[C:39]([C:43]5[CH:48]=[CH:47][N:46]=[C:45]([N:1]6[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]6)[N:44]=5)[CH:40]=[CH:41][CH:42]=4)=[CH:35][N:36]=3)[N:33]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O[C@@H]1CCNC1
Reactant: CS(=O)(=O)c1nccc(-c2cccc(-c3cnc4ccc(N5CCC[C@@H]5c5cccc(F)c5)nn34)n2)n1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCN(c2nccc(-c3cccc(-c4cnc5ccc(N6CCC[C@@H]6c6cccc(F)c6)nn45)n3)n2)C1
Temperature: 120 °C

Procedure:
In step 14-3, (R)-pyrrolidin-3-ol (136 mg, 1.56 mmol) and DIEA (453 uL, 2.6 mmol) were added to a solution of (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (14-3) (268 mg, 0.52 mmol) in DMSO (3 mL). The mixture was heated to 120° C. for 1 hour. The mixture was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography (silica gel, CH2Cl2/CH3OH, 5% gradient) to give (R)-1-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)pyrimidin-2-yl)pyrrolidin-3-ol (14-4). LC/MS: 523.2 (MH+).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>CN1CCCC1=O>[CH3:1][N:2]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: Brc1ncccn1
Reactant: CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ncccn1)[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1

Procedure:
(R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was reacted with potassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) in N-methylpyrrolidone (3 ml) at 100° C. for 4 hours. The reaction solution was then partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.04 (C27H31ClN6O); MS (ESI): 491 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[CH:14]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:21][CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: OCC1CCCCC1
Product: CNc1ccc(Br)c(OCC2CCCCC2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 11, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and cyclohexanemethanol as the starting materials. LCMS calculated for C14H20BrN2O3 (M+H)+: m/z=343.1, 345.1. found: 343.0, 345.1.
Reaction SMILES: [CH:1]1([Na:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.C[O:8][C:9](=O)[CH3:10]>O1CCCC1>[C:9]([C:1]1([Na:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:8])[CH3:10]
Reactant: [Na]C1C=CC=C1
Reactant: COC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C1([Na])C=CC=C1

Procedure:
In accordance with the Rausch method, 10 ml of a tetrahydrofuran solution of cyclopentadienyl sodium (20 mmol/10 ml THF) and 4 ml of methylacetate were mixed in a nitrogen atmosphere, and refluxed for 20 minutes to obtain acetylcyclopentadienyl sodium. To the solution containing colorless crystals thereby obtained, 40 ml of benzene was added, and 10.6 g of tris-triphenylphosphine cobalt monochloride was further added whereby a red solution of bistriphenylphosphine-η5 -acetylcyclopentadienyl cobalt was immediately obtained. The solution was stirred at room temperature for about 1 hour. Then, an aqueous ammonium chloride solution was added to remove the excess acetylcyclopentadienyl sodium by transferring it to the aqueous phase. The organic phase was dried over sodium sulfate and then filtered. To the solution thereby obtained, 5 ml of 1,5-cyclooctadiene was added, and the mixture was refluxed for 1 hour on a hot water bath, and then concentrated under reduced pressure. The product was subjected to alumina column chromatography, whereupon an orange brown fraction eluted by a mixture of benzene/hexane (1:1) was isolated. The solvent was distilled off, and the product was recrystallized from benzene/hexane to obtain 0.32 g of brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1COCC1.O.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 1.5 h
Yield: 23.4 %

Procedure:
A solution of [1-(3,4-dichloro-phenyl)-1H-imidazol-4-yl]-methanol (10.8 g, 44.3 mmol) in a mixture of THF (270 ml) and H2O (30 ml) was treated with manganese(IV) oxide (5 g, 57.5 mmol) and the mixture was refluxed for 4 h. A second portion of manganese(IV) oxide (1.5 g) was added and reflux continued for 1.5 h. The mixture was filtered over Celite, and the residue was washed with MeOH. Toluene was added to the filtrate, and the H2O was removed azeotropically. The brown residue was taken up in CH2Cl2 and upon standing white crystals formed. Filtration afforded 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carbaldehyde (2.5 g, 25%). MS: m/e=240.0 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1.Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39])=[O:27].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=1)[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=1[C:38]([F:39])([F:40])[F:41])=[O:27]
Reactant: COCCNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reactant: CC(C)c1ccc(NC(=O)CBr)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
0.533 g (1.65 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (Example III-33) is initially charged in 6 ml of dimethylformamide. At room temperature, 0.588 g (1.81 mmol) of 2-bromo-N-[4-isopropyl-2-(trifluoromethyl)phenyl]acetamide (Example III-17) and 0.152 g (1.81 mmol) of sodium bicarbonate are added. The mixture is set at 90° C. for 2 hours. The reaction mixture is then allowed to cool, and water is added. The mixture is extracted once with ethyl acetate and the organic phase is washed three times with water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (cyclohexane/ethyl acetate 4:1) and the product is then dried under reduced pressure. This gives 0.885 g (95% of theory) of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=1[S:36](=[O:39])(=[O:38])[NH2:37]>O.O1CCOCC1>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[C:28]([S:36](=[O:38])(=[O:39])[NH2:37])[CH:29]=2)[NH2:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NN(C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 56.4 %

Procedure:
By using the process of Example 1(B), 28 g of 4-benzoyl-2-nitrophenylhydrazine, 272 ml of dioxane, 5.8 g of anhydrous sodium carbonate dissolved in 110 ml of water and 27.6 g of 4-chloro-3-sulfamoylbenzoyl chloride dissolved in 217 ml of dioxane were used as starting materials to yield 29.1 g (61%) of 4-benzoyl-2-nitro-N-(4'-chloro-3'-sulfamoylbenzoyl)phenylhydrazine, m.p.: 148° C. after recrystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Te:11]([Cl:14])(Cl)Cl)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:15]([O-])([OH:17])=[O:16].C(O)C.[PH2](O)=O>C(O)(=O)C>[Cl:14][TeH:11]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=2[NH+:15]([O-:17])[O:16]1
Reactant: COc1ccc([Te](Cl)(Cl)Cl)cc1OC
Reactant: O=[N+]([O-])O
Agent: O=[PH2]O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)[TeH](Cl)O[NH+]2[O-]
Reaction time: 1 h

Procedure:
3,4-Dimethoxyphenyltellurium trichloride (74 g=0.2 mole) was suspended in glacial acetic acid (200 ml) in a 1500 ml Erlenmeyer flask. Nitric acid (18 g of 70%=0.2 mole) was added gradually to the stirred mixture, which caused formation of a clear, red solution and a mildly exothermic reaction. Stirring was continued for one hour at room temperature, then ethanol (1000 ml) and hypophosphorous acid (24.0 g of 50 weight percent aqueous) were added in order. Over a period of 30 minutes there occurred crystallization of a red solid, which was collected by filtration to give 47.3 g, 68.8% of theory, m.p. 199°-200° C. The material was identical to product isolated by procedure A. Elemental analyses were in agreement with that calculated for the structural formula.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.3 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added piperidin-4-ol (30 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC followed by a second chromatography purification (silica gel, gradient 1/1 ethyl acetate/isohexane) yielding Compound 55 as a solid (10 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.Br[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)ccc1OC(C)c1ccccc1

Procedure:
A solution of methyl 5-bromosalicylate (12.70 g, 55 mmol), (1-bromoethyl)benzene (7.05 mL, 50 mmol), and K2CO3 (20.73 g, 150 mmol) in acetone (250 mL) is refluxed 18 hours. The mixture is then filtered and the filtrate is concentrated in vacuo. The residue is dissolved in EtOAc (250 mL) and then washed with 1 N NaOH (2×150 mL) and brine (1×100 mL), and dried over MgSO4. Concentration in vacuo yields methyl 5-bromo-2-(1-phenylethoxy)-benzoate.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])([OH:3])=[O:2].[CH2:24](O)[CH3:25].C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C1C=CC=CC=1>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:17])([O:3][CH2:24][CH3:25])=[O:2]
Reactant: O=C(O)CSCCCCCCCCCCC(=O)N1CCOCC1
Reactant: CCO
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: c1ccccc1
Product: CCOC(=O)CSCCCCCCCCCCC(=O)N1CCOCC1

Procedure:
6 g (0.017 mole) of 11-(Carboxymethylthio)undecanoylmorpholine, 4.8 g (0.11 mole) of anhydrous ethyl alcohol and 1 g of 2-naphthalenesulfonic acid were placed in a flask equipped with reflux condenser, and refluxed for 16 hours. The mixture was dissolved in benzene, washed with water, dried over anhydrous sodium sulfate, filtered, passed through a column of activated alumina and stripped of solvent. The product, 11-(carbethoxymethylthio)undecanoylmorpholine, had a nitrogen content of 3.66% (theory, 3.75%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[OH-].[Na+].O1CCCC1>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1
Reactant: CCOC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 30 %

Procedure:
A mixed solution of ethyl 1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidine-4-carboxylate (60.0 mg, 0.124 mmol), an aqueous 1 N sodium hydroxide solution (0.992 ml, 0.992 mmol), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at 80° C. for 5 hours. The solvent was distilled off under reduced pressure. The residue was adjusted to pH 3 by addition of an aqueous 1 N sodium hydroxide solution. A solid was separated by filtration and washed with water to give 17.0 mg (30.0%) of the desired product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: COC(=O)c1cccc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (164a) (116.41 mg, 0.44 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (73 mg, 0.42 mmol), WSC hydrochloride (241.23 mg, 1.26 mmol) and HOBt (56.72 mg, 0.42 mmol), to obtain 148.3 mg of the title compound as a pale yellow oily substance (81%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1.C(#N)C.[CH3:25][CH2:26][CH2:27]CCCC>CN(C=O)C.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>[NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8]([CH2:27][CH:26]=[CH2:25])[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cccc(Br)c31)CC(N)CC2
Reactant: CCCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cccc2c3c(n(CC(=O)OCC)c12)CCC(N)C3
Temperature: 25 °C

Procedure:
To a stirred and degassed solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.2 mmol) and Pd(PPh3)4 (0.02 mmol, 0.1 eq.) in dry DMF (1.5 ml) is added under inert atmosphere the appropriate tetraC1-5-alkyltin or allyltrialkyltin, respectively (0.22 mmol, 1.1 eq.). The reaction mixture is allowed to stir overnight at 110° C. After cooling to rt, acetonitrile (1 ml) and heptane (1 ml) are added. The acetonitrile-DMF phase is washed three times with heptane. Water is then added and the resulting aq. phase is extracted twice with AcOEt. The combined org. phases are washed with brine and dried over Na2SO4. Evaporation of the solvent in vaccuo yields the protected ethyl (3-amino-8-C1-5-alkyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative or ethyl (3-amino-8-allyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1, respectively.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH:24]([C:27]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:31]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C:30]([CH2:45][OH:46])=[C:29]([CH:47]([CH3:49])[CH3:48])[N:28]=1)([CH3:26])[CH3:25]>ClCCl>[CH:24]([C:27]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:31]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[C:30]([CH2:45][O:46][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[C:29]([CH:47]([CH3:48])[CH3:49])[N:28]=1)([CH3:26])[CH3:25]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COC2CCCCO2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1.88 g (22.4 mmol) of dihydropyran and 0.525 g (1.49 mmol) of pyridinium p-toluene-sulphonate are added to a solution of 5.36 g (14.9 mmol) of the compound from Example 4 in 100 ml of dry dichloromethane and the mixture is heated to reflux for 48 hours. After cooling to room temperature, the mixture is diluted using dichloromethane and extracted several times using water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using dichloromethane).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[S:2].N[C:14]1C=NC=C[C:19]=1[C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([CH3:26])[CH:25]=1>C1COCC1.CCOC(C)=O>[N:8]([C:12]1[CH:11]=[N:10][CH:9]=[CH:14][C:19]=1[C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:23]=[C:24]([CH3:26])[CH:25]=1)=[C:1]=[S:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N=C=S)c1
Temperature: 60 °C
Yield: 48.7 %

Procedure:
tert-butyl (3-(3-isothiocyanatopyridin-4-yl)-5-methylphenyl) carbamate. 1,1′-thiocarbonyldiimidazole (155 mg, 0.78 mmol, Sigma-Aldrich) was added to a solution of tert-butyl (3-(3-aminopyridin-4-yl)-5-methylphenyl)carbamate (117 mg, 0.39 mmol) in THF (4 mL) at RT. The reaction mixture was heated at 60° C. for 2 h. The mixture was cooled to RT, diluted with EtOAc, washed with water and the organic layer was dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to provide tert-butyl (3-(3-isothiocyanatopyridin-4-yl)-5-methylphenyl)carbamate (63 mg, 0.19 mmol, 47% yield) as a white solid. MS (ESI, pos. ion) m/z: 342.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (s, 1 H), 8.49 (d, J=5.09 Hz, 1 H), 7.32-7.37 (m, 2 H), 7.29 (s, 1 H), 6.98 (s, 1 H), 6.56 (s, 1 H), 2.41 (s, 3 H), 1.53 (s, 9 H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=1[O:24][CH3:25].O.NN>CO>[NH2:3][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][C:13]=1[O:24][CH3:25]
Reactant: COc1cc(S(=O)(=O)N(C)C)ccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(S(=O)(=O)N(C)C)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
4-(1,3-Dioxoisoindolin-2-yl)-3-methoxy-N,N-dimethylbenzenesulfonamide (Preparation 105, 50 mg, 0.139 mmol) was suspended in MeOH (6 mL) and hydrazine hydrate (1 mL) was added. The resulting solution was stirred at room temperature for 2 hours before concentrating in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 50% EtOAc in cyclohexane to give the title compound as white solid (11 mg, 34%).