Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:22])=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.O1CCOCC1.[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:29]([S:36][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:22])=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(Cn2cc(Cl)c3ccc(Br)cc3c2=O)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(Cl)c3ccc(SCc4ccccc4)cc3c2=O)cc1
Temperature: 80 °C
Yield: 89.7 %

Procedure:
A screw cap vial was charged with 7-bromo-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (3.6 g, 9.51 mmol), Xantphos (0.275 g, 0.475 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.218 g, 0.238 mmol), 1,4-Dioxane (9.51 ml) and dipea (3.31 ml, 19.02 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to room temperature and benzyl mercaptan (1.18 ml, 9.98 mmol) was added and the reaction was continued heating at 80° C. for an additional 30 minutes. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 3.60 g of 7-(benzylthio)-4-chloro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one. m/z (ESI) 442.1 (M+H)+.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:53][C:49]([CH2:50][CH2:51][OH:52])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(CCO)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(CCO)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-aminophenethyl alcohol as the aniline component. (41%, MS=500.2 (M+H))
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:24](=[O:34])[C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNC(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Prepared using General Procedure 4: To a stirring solution of 4-((4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-2 (857 mg, 1.75 mmol) in DMF (7 mL) was added sodium hydride (77.0 mg, 1.92 mmol). After 5 min, tert-butyl 2-bromoacetate (0.30 mL, 2.01 mmol) was added. After stirring at room temperature for 1 h, additional tert-butyl 2-bromoacetate (0.297 mL, 2.01 mmol) and sodium hydride (77.0 mg, 1.92 mmol) were added and the reaction stirred for another 1 h. The reaction mixture was diluted with EA (100 mL) and washed with brine (200 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to provide 888 mg (84%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-3. LCMS-ESI (m/z) calculated for C34H40N2O8: 604; no m/z observed, tR=3.62 min (Method 5).
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[CH2:25]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N(C(=O)c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2 g, 0.006 M) in DMF (25 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.3 g, 0.007 M). The mixture was stirred at room temperature for 0.5 hours, and then benzyl bromide (1.2 g, 0.007 M) was added dropwise. The reaction mixture was warmed to 60° C. and allowed to stir for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl, and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate, and the methylene chloride removed under vacuum to afford N-benzyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13]([Cl:15])=[O:14].[F:16]C1C=C(F)C=C2C=1CC/C/2=C\C(O)=O>>[F:16][C:10]1[CH:2]=[C:3]2[C:7](=[CH:8][CH:9]=1)/[C:6](=[CH:12]/[C:13]([Cl:15])=[O:14])/[CH2:5][CH2:4]2
Reactant: O=C(O)/C=C1\CCc2c(F)cc(F)cc21
Reactant: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Product: O=C(Cl)/C=C1\CCc2cc(F)ccc21

Procedure:
This compound was prepared in a similar manner to (E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride in Example 5f by substituting (E)-2-(5-fluoro-1-indanylidene)acetic acid (5.77 g, 0.03 mol) for (E)-2-(4,6-difluoro-1-indanylidene)acetic acid. The resulting solution was concentrated in vacuo, and the residue was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OC1CCNCC1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CCN(C2CCCC2)CC1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
4-Hydroxypiperidine (2.08 g, 21.2 mmol), K2CO3 (5.86 g, 2 eq.), cylopentylbromide (11.51 g, 77.6 mmol, 3.7 eq.) and MeOH (20.8 ml) were refluxed together overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (40 ml) and extracted with TBME (40 ml). The aqueous phase was basified to pH 14 with a 2M NaOH solution and extracted with DCM (4×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give 1-cyclopentyl-4-hydroxypiperidine (2.55 g, 71%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.C[O-].[Na+].Cl.Cl.[NH2:17][C:18]1[C:23](N)=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>CO>[OH:25][C:19]1[C:18]2[NH:17][C:8]([CH2:7][O:6][C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(O)c1N
Reactant: N#CCOc1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12

Procedure:
In a 50 ml single neck round bottom flask, under a nitrogen atmosphere, 4-chlorophenoxyacetonitrile (0.46 g, 2.79 mmol) was admixed in methanol (11 ml). The contents were stirred to achieve dissolution. To this solution were added sodium methoxide (0.164 g, 3.0 mmol). The resulting mixture was stirred for about 40 minutes. To this mixture was added 2,3-diaminophenol dihydrochloride salt (0.5 g, 2.5 mmol) and the resulting mixture was stirred for two hours at room temperature. The reaction mixture was filtered and the filtrate was added to 60 ml of water. A light brown precipitate formed and this precipitate is removed by filtration, and washed with 20 ml of water. The solid was dried in a vacuum oven overnight.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.C(O)C.[Pd]>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(F)c2c1C=CN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 91.1 %

Procedure:
Dissolve 9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-benzo[d]azepine (9.4 g, 32.4 mmol) with 10% Pd/C (dry basis, Degussa type, 1.4 g, 0.65 mmol) in EtOAc/ethanol (1:1, 200 mL) and stir at ambient temperature under a balloon of hydrogen for 4.5 h. Filter the mixture through a pad of silica gel and evaporate the filtrate to obtain the desired intermediate (8.6 g, 91%). MS (ES+) m/z: 292 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[CH3:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([S:10][CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(C#N)ccc(S)c1C#N
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(C#N)c(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 g (0.29 mol) of 3-methyl-2,4-dicyanothiophenol were added to a solution of 23 g (0.58 mol) of NaOH in 400 ml of water, and 73 g (0.58 mol) of dimethyl sulfate were then added dropwise at 25-35° C. The mixture was stirred at 25° C. for 16 h, after which a solid had precipitated out, which was filtered off with suction, washed twice with water and then recrystallized from glacial acetic acid/water. Yield: 43 g (80%).
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C(O)C.O>C1(C)C=CC=CC=1>[CH3:3][N:2]([CH:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])[CH3:1]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN(C)C(c1ccccc1)C1CCCCC1O
Yield: 86.4 %

Procedure:
3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 (2nd stage), dissolved in 26 ml toluene, were added dropwise to 26 ml (39 mmole) diisobutylaluminium hydride (1.5 M in toluene) at RT under nitrogen. The mixture was heated under reflux for 15 hours, while stirring. For working up, 13 ml ethanol and 13 ml water were slowly added dropwise and the suspension was stored at 0° C. for several hours, filtered through a glass frit and washed several times with a little toluene. The filtrate was concentrated on a rotary evaporator (500 to 10 mbar) and residues of solvent were removed under a high vacuum (approx. 0.1 mbar). 2.62 g (86.6% of theoretical) 2-(dimethylaminophenylmethyl)-cyclohexanol were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C1C=CC=CC=1.O>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CC2CC2(c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
A 19.35 g. portion of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane is dissolved in 150 ml. of benzene. A 10.59 g. portion of sodium carbonate in 100 ml. of water is added with stirring. An 18.45 g. portion of p-nitrobenzoyl chloride in 100 ml. of benzene is added slowly to the rapidly stirred mixture. The mixtue is stirred for 1 hour and then allowed to stand overnight at room temperature. The product is recovered by filtration, washed successively with dilute sodium carbonate, 0.5N hydrochloric acid and then water and dried yielding the product as a white solid, mp 177°-180° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](OCC)=[O:9])[C:3]1=[O:13].[CH3:14][NH2:15]>O>[CH3:14][NH:15][C:8](=[O:9])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: CN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Solvent: O
Product: CNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)-acetate is treated with 10 ml of a 40% solution of methylamine in water. After stirring at room temperature for 1 hour, the mixture is evaporated. The residue is shaken five times with acetonitrile in order to remove the water, whereupon in each case it is again evaporated. The residue is treated with diethyl ether. By filtration there is isolated N-methyl-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)-acetamide of melting point 129°-130.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=3)[O:36]2)=[CH:31][CH:30]=1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:44][CH:43]([OH:45])[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:41]=3)[O:36]2)=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: COc1ccc(C2CC(O)c3cc(O)ccc3O2)cc1
Product: COc1ccc(C2CC(O)c3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1

Procedure:
2-(4-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(4-methoxyphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.40 (d, 2H, J 8.7 Hz), 7.24 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, J 9.1 Hz), 7.00 (dd, 1H, J 8.7, 2.8 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.84 (d, 1H, J 8.7 Hz), 5.63 (d, 1H, J 6.4 Hz), 5.23 (d, 1H, J 10.8 Hz), 4.95-5.02 (m, 1H), 3.78 (s, 3H), 2.25-2.29 (m, 1H), 1.98-2.04 (m, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38]>ClCCl>[O:38]=[C:33]1[CH2:34][CH2:35][CH2:36][CH2:37][N:32]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH:24]=[O:23]
Reactant: O=C1CCCCN1c1ccccc1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1ccccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dess Martin periodinane (3.36 g, 7.91 mmol, 1.3 eq) is added portionwise under stirring to 1-[2-(2-hydroxyethyl)phenyl]piperidin-2-one a2-2 (1.33 g, 6.09 mmol, 1 eq) in dichloromethane (40 ml). After a few hours additional Dess Martin periodinane (1.29 g, 3.04 mmol, 0.5 eq) is added and the reaction mixture is stirred overnight at room temperature, then filtrated and evaporated to dryness to afford crude [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1, which is used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:22]2=[O:24])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c12
Yield: 104.2 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide (302 mg, 0.901 mmol) and triphosgene (321 mg, 1.081 mmol) in THF (20 mL) was stirred at room temperature for 2 h. The mixture was treated carefully with saturated aqueous NaHCO3 and stirred until gas evolution ceased. The mixture was extracted twice with DCM, and the combined organic phases were washed with water, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (339 mg) which was used without further purification. Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OCCCO2)=[CH:19][CH:18]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>CC#N.O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: Clc1ccc(B2OCCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1OC
Temperature: 150 °C
Yield: 72.2 %

Procedure:
To a solution of methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (200 mg, 0.852 mmol) in CH3CN (1.246 mL) and H2O (1.246 mL) were added 2-(4-chlorophenyl)-1,3,2-dioxaborinane (251 mg, 1.279 mmol), KF (149 mg, 2.56 mmol), palladium(II) acetate (Pd(OAc)2; 19.14 mg, 0.085 mmol), and triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (100 mg, 0.170 mmol). The reaction mixture was then heated in a bench top Biotage microwave at 150° C. for 5 min. The reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude residue was purified by normal phase chromatography (eluting with 10% EtOAc/40% CH2Cl2/50% hexanes) to afford the title compound as a tan solid (191 mg, 72.1%): mp 93-94° C.; 1H NMR (400 MHz, acetone-d6) δ 7.96 (dd, J=8.8, 1.4 Hz, 2H), 7.57-7.49 (m, 2H), 5.93 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), ESIMS m/z 311 ([M+H]+), 309 ([M−H]−).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].[OH-:29].[Na+].OO>O1CCCC1.O.C(O)C>[OH:29][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: C=CCCCCn1c2ccccc2c2ccccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
200 ml of a solution of 9-borabicyclo[3.3.1]-nonane (9-BBN) in tetrahydrofuran (0.5 mol/1) were initially taken in a thoroughly heated 500 ml three-necked flask. After the dropwise addition of a solution of 100 mmol of N-5-hexenylcarbazole in 100 ml of dry tetrahydrofuran, the mixture was stirred for 3 hours at room temperature, after which 60 ml of ethanol, 20 ml of 6 N sodium hydroxide solution and 40 ml of hydrogen peroxide (30% strength) were added in succession. Refluxing was carried out for 1 hour, after which the reaction mixture was worked up by adding 200 ml of water and then stripping off the tetrahydrofuran. The resulting N-(6-hydroxyhexyl)-carbazole was extracted with ether, the ether extract was dried and the ether was evaporated. The resulting crude product was then recrystallized from 9:1 hexane/acetone. The pure N-(6-hydroxyhexyl)-carbazole obtained in 61% yield was in the form of white crystals.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH2:24](I)[CH3:25]>>[CH2:24]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])[CH3:25]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CCI
Product: CCN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a off-white solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and ethyl iodide. MS (ESI): 357.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:23])[CH2:19][CH:18]1[C:20](Cl)=[O:21]>O1CCCC1>[CH3:16][C:17]1([CH3:23])[CH2:19][CH:18]1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21]
Reactant: CC1(C)CC1C(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CC2(C)C)cc1
Yield: 65.7 %

Procedure:
Using a method similar to that of Example 4, 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are reacted with 4.7 g (35.4 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 150 ml of absolute tetrahydrofuran. The mixture is concentrated to about 70 ml, water is added and the product is filtered off, washed with water and recrystallized twice from dimethylformamide/water, giving 5.8 g (66% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-5-methyl-3(2H)-pyridazinone as colorless crystals, of melting point 222°-223° C.