Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[B:17](OCCCC)([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[B:17]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCOB(OCCCC)OCCCC
Product: CCCCOB(OCCCC)Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C

Procedure:
In a moisture-protected atmosphere, 2,6-di-tert-butyl-4-methylphenol (1543 g) was heated to 245° C. and while stirring tributyl borate (805.5 g) was slowly added drop by drop. The addition rate was controlled to maintain the reaction temperature at 230°-250° C. and butanol was distilled from the mixture as formed. The distillate was fractionated to separate butanol from tributyl borate and the latter was recycled to the reacting mixture. The reaction mixture was heated at 250°-260° C. until no further distillation was observed.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]3[C:10]4[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:12](=[O:22])[C:11]=4[CH:23]=[CH:24][CH:25]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[OH:33][C:34]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:35]=1[CH:36]=O>C(Cl)Cl.CO>[OH:33][C:34]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:35]=1/[CH:36]=[N:1]\[C:2]1[C:7]2=[CH:8][C:9]3[C:10]4[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:12](=[O:22])[C:11]=4[CH:23]=[CH:24][CH:25]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: CN(C)CCN1C(=O)c2cccc3cc4c(N)cccc4c(c23)C1=O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)CCN1C(=O)c2cccc3cc4c(/N=C\c5cc(O)ccc5O)cccc4c(c23)C1=O
Yield: 88.2 %

Procedure:
A mixture of 50 mg (0.150 mmole) of 8-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 4), 5 mL of toluene and 25 mg (1.2 molar equivalent) of 2,5-dihydroxybenzaldehyde was refluxed for 3 hours. After cooling, toluene was evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 and then a 90:10 volume ratio), thus resulting in 60 mg (yield: 88%) of the desired product (formula below) as a deep red powder.
Reaction SMILES: [H-].[H-].COCCO[Al+]OCCOC.[Na+].N1CCOCC1.[CH3:21][O:22][CH2:23][O:24][CH2:25][C:26]1[N:31]2[CH:32]=[CH:33][N:34]=[C:30]2[C:29]([C:35](OC)=[O:36])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:21][O:22][CH2:23][O:24][CH2:25][C:26]1[N:31]2[CH:32]=[CH:33][N:34]=[C:30]2[C:29]([CH:35]=[O:36])=[CH:28][CH:27]=1
Reactant: COCOCc1ccc(C(=O)OC)c2nccn12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COCOCc1ccc(C=O)c2nccn12
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 56.2 %

Procedure:
To a stirred solution of sodium bis(2-methoxyethoxy)aluminium dihydride (65% wt. in toluene, 0.512 mL, 1.678 mmol) at 0° C. under a nitrogen atmosphere was added a solution of morpholine (0.147 mL, 1.678 mmol) in toluene (3.35 mL) dropwise over 15 min to give a solution of reducing agent (approx 4 mL, 4 eq). An aliquot of this solution (1.5 mL, ca 1.5 eq) was added dropwise over 2 min to a stirred solution of impure methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (105 mg, 0.420 mmol) in toluene (4 mL) at −40° C. The reaction was stirred at −40° C. for 40 min when LCMS indicated that the ester had been reduced to the aldehyde. The reaction was quenched carefully by addition of water (2 mL) and then allowed to warm to ambient temperature and concentrated in vacuo. The residue was pre-absorbed on florosil (100-200 mesh) and purified on a silica cartridge (20 g) using a 0-25% methanol-DCM gradient over 40 min. The appropriate fractions were combined and concentrated in vacuo to give impure 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carbaldehyde as a yellow oil (52 mg) which was used directly in the next step.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nc3)CC2)c(C)c1
Yield: 76.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (389 mg) described in Preparation Example 145 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (313 mg) was obtained.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[K].[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29]Br)=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C.O>[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29][NH2:5])=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCOc1ccc2c(c1)C=C(CBr)CO2
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.25 g (6.75 mmol) of potassium phthalimide are added to a solution of 1.4 g (4.5 mmol) of the brominated compound obtained in Step D in 15 ml of DMF; the medium is then stirred overnight at ambient temperature and under argon. After evaporation of the solvent in vacuo, the residue obtained is taken up in water; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) allows access to the title phthalimide in the form of a white solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.S(Cl)([Cl:20])=O>ClCCl>[CH3:17][O:16][C:13]1[N:14]=[CH:15][C:10]([NH:9][C:5]([CH2:4][CH2:3][CH2:2][C:1]([Cl:20])=[O:8])=[O:7])=[CH:11][CH:12]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COc1ccc(N)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCCC(=O)Cl)cn1
Reaction time: 1 h

Procedure:
Glutaric anhydride (1.14 g, 10.0 mmol) was added to a solution of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) in dichloromethane (25 mL). After standing for 1 hour at room temperature, thionyl chloride (5.95 g, 50.0 mmol) was added, followed by heating to reflux for 0.5 hour. The solvent and excess thionyl chloride were evaporated in vacuo, yielding 4-(6-methoxy-pyridin-3-ylcarbamoyl)-butyryl chloride, which was used without further purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a mixture di-tert-butyl [{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidin-1-yl}methylylidene]biscarbamate 64 (2.30 g, 4.71 mmol) in a solution of DCM (40 mL) and ethanol (6 mL) was added hydrazine hydrate (0.270 mL, 4.71 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 65 (0.72 g, 43%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][OH:8])[N:6]=1.C([OH:17])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([C:7]([OH:17])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1CO
Reactant: CC(C)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of ethyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (2.5 g, 11 mmol, Intermediate 215) in acetone at 0° C. was slowly added a solution of chromium trioxide (2.26 g, 22 mmol) in 20% conc. Sulfuric acid in water (20 mL). After stirring at room temperature for 2 hrs, isopropanol (1 mL) was added to quench unreacted chromium trioxide. The reaction was diluted with water and the acetone was removed. Partitioning with methylene chloride (×3), drying with MgSO4 and concentrating yielded a white solid (2.3 g, 90%). MS (ES) MH+: 236 for C7H6ClNO4S; NMR: 1.26 (t, 3 H) 4.31 (q, 2 H) 13.99-14.15 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7](C(O)=O)=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.CC(=O)OCC>[OH-].[Na+]>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1ccn(C2CC2)c2nc(Cl)c(F)cc12
Reaction time: 1 h

Procedure:
7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (2.0 g) was added portionwise to a boiling solution of Dowtherm (50 ml heated at 250° C.) and further stirred at this temperature for 1 h. The reaction mixture was allowed to reach rt and diluted with 1N NaOH (100 ml) and extracted with EA. The org. phase was discarded. The aq. phase was acidified with 3N HCl and extracted with ether/EA. The aq. layer was filtered and the filtrate was extracted with ether/EA. The combined org. layers were washed with water and brine dried over MgSO4, filtered and evaporated under reduced pressure affording a solid which was stirred in Hept/EA and filtered. The filtrate was concentrated under reduced pressure and purified by CC (EA to EA/MeOH 9:1), affording a beige solid.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:24])[CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C([BH3-])#N.[Na+]>>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:18][C:19]=2[CH3:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCC(=O)C1
Reactant: Cc1cc(-n2ccnc2)ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCN1CCCC(Nc2ccc(-n3ccnc3)cc2C)C1

Procedure:
In a manner similar to Preparation 8, react 1-butyl-3-piperidinone with 4-(1H-imidazol-1-yl)-2-methylbenzenamine and sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.N1C=CC=CC=1.CN(C)C=O>O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]3[NH:34][N:33]=[N:32][N:2]=3)[O:4][C:5]=2[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(COc2ccc3nc(-c4nnn[nH]4)oc3c2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
2-cyano-6-(3-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazole (2.97 mmoles), sodium azide (965 mg), pyridine hydrochloride (1.72 g) and dimethylformamide (7 ml) are combined and heated at 100° C. for 48 hours. The reaction mixture is poured into cold water and the resulting precipitate is collected. The precipitate is dissolved in hot ethanol and reprecipitated by addition of water to give 5-(6-(3-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazol-2-yl)tetrazole.
Reaction SMILES: [P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])([O:3]CC)=O.[CH2:12]([O:19][C:20]1[C:29]([CH2:30]Br)=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([O:32][CH3:33])=[N:27]2)=[N:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][P:1]([CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[N:27]=2)[N:22]=[CH:21][C:20]=1[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[O:6][CH2:7][CH3:8])[CH3:11]
Reactant: COc1ccc2ncc(OCc3ccccc3)c(CBr)c2n1
Reactant: CCOP(=O)(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1c(OCc2ccccc2)cnc2ccc(OC)nc12)OCC
Yield: 77.2 %

Procedure:
Triethyl phosphate (960 μL, 5.60 mmol, 10.0 eq) is added at room temperature to a stirred solution of 7-benzyloxy-8-bromomethyl-2-methoxy-[1,5]naphthyridine (200 mg, 0.56 mmol, 1.0 eq) in toluene (1 mL) and the resulting mixture is heated under reflux for 6 hours. Solvent is then removed and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester as a yellow oil (180 mg, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[CH:14](=O)[CH3:15]>Cl(O)(=O)(=O)=O>[CH3:14][C:15]1[N:1]=[C:2]2[N:6]([C:8]=1[NH:7][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][S:3]2
Reactant: Nc1nccs1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CNc1c(C)nc2sccn12

Procedure:
Compound 23 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) methyl isocyanoacetate solution (0.2 M, MC), 0.500 ml (0.15 mmol) acetaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [OH:1][NH:2][CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:4]([NH2:6])=[O:5].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=O.N1C=CC=CC=1>CN(C)C(=O)N(C)C>[OH:1][N:2]1[CH:3]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:4](=[O:5])[N:6]=[C:18]([CH3:20])[C:17]1=[O:21]
Reactant: NC(=O)C(Cc1c[nH]c2ccccc12)NO
Reactant: CC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C(=O)N(C)C
Product: CC1=NC(=O)C(Cc2c[nH]c3ccccc23)N(O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
In 5 ml of tetramethylurea was dissolved 0.22 g of 2-hydroxylamino-3-(indol-3-yl)propionic acid amide. The solution was cooled to -5° to 0° C. Thereto was added 0.1 g of pyruvic acid chloride. Then, there was added 1 ml of a tetramethylurea solution containing 90 mg of pyridine. The mixture was stirred for 1.5 hours with ice cooling and for 1 hour at room temperature. The mixture was poured into ice water. The resulting mixture was subjected to extraction with CHCL3. The extract was washed with water, dried over magnesium sulfate, and subjected to TLC (methanol/CH2Cl2 =1/10). The fraction separated was heated for 10-20 minutes at 80° C. under vacuum. The residue was mixed with methanol for crystallization. The resulting crystals were recrystallized from methanol to obtain 40 mg of colorless needle-like cyrstals. Yield: 15%. MS (m/e):M30 271. Melting point: 166°-168° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[N:22]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([C:28]2[CH:29]=[CH:30][C:31]([NH:32][S:2]([C:5]3[CH:14]=[CH:13][C:12]4[NH:11][C:10](=[O:15])[C:9]5[NH:16][CH:17]=[CH:18][C:8]=5[C:7]=4[CH:6]=3)(=[O:3])=[O:4])=[CH:33][CH:34]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Nc3ccc(N4CCOCC4)cc3)cc2c2cc[nH]c12
Yield: 49.8 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 98 mg (0.55 mmol) of 4-morpholin-4-yl-aniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in methanol, 57 mg (25%) of 8-(4-morpholin-4-yl-phenylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a gray solid.
Reaction SMILES: B(Br)(Br)Br.[C:5]1([C:11]2[N:12]=[C:13]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35]C)[CH:30]=3)[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([C:11]2[N:12]=[C:13]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=3)[O:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CN2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CN2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 3 h
Yield: 91.2 %

Procedure:
A 1.0 M solution of boron tribromide in methylene chloride (2.08 ml) was added dropwise to a solution of 2-(4,5-diphenyl-2-oxazolyl)-1-(3-methoxybenzyl)piperidine (440 mg) in methylene chloride (2.5 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 3 hours and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-(4,5-diphenyl-2-oxazolyl)-1-(3-hydroxybenzyl)piperidine (388 mg) as a pale yellow powder. FABMS (m/z): 410 (M+) mp: 204.7-208.3° C. IR (Film): 1600, 1585, 1255 cm-1NMR (CDCl3, δ): 1.2-1.95 (6H, m), 2.0-2.25 (1H, m), 3.05-3.11 (1H, m), 3.25-3.37 (1H, m), 3.73-3.81 (2H, m), 6.71-6.83 (3H, m), 7.13 (1H, q, J=7.7 Hz), 7.25-7.48 (11H, m)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:18]=[CH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a solution of 2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydrospiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one (1.0 g) in chloroform (20 mL), trifluoroacetic acid (20 mL) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated. The residue was dissolved in methanol and hydrogenated with 4M hydrogen chloride/ethyl acetate in the presence of 20% palladium carbon at 1 atm of hydrogen for 14 hours. The catalyst was removed by filtration and the filtrate was concentrated. To the residue, aqueous 1N sodium hydroxide (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane (10 mL) were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (200 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14](I)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>C(O)C.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([NH:7][C:8]([C:10]2[C:14]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:32][OH:31])[CH:38]=3)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: COc1ccc(Cn2cc(I)c(C(=O)Nc3ccccc3)n2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(-c3cccc(CO)c3)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 131.9 %

Procedure:
A mixture of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide (50 mg; 0.11 mmol), bis(tri-tert-butylphosphine)palladium (12 mg), potassium carbonate (100 mg; 0.66 mmol) and 3-(hydroxymethyl)benzene boronic acid (21 mg; 0.14 mmol) in ethanol/toluene/water (4 ml:1 ml:1 ml) was heated at 120° C. (50 W) for 15 minutes in a CEM Discover microwave synthesiser. The reaction was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated and the crude material purified by flash column chromatography eluting with 1:2 then 2:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 60 mg of 4-(3-hydroxymethyl-phenyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]([N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])/[C:11](=[N:20]/[C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[F:32])/[S:10]1)([CH3:8])([CH3:7])[CH3:6].[CH3:34][Mg]Br>C1COCC1>[C:5]([N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])([CH3:34])[CH3:18])/[C:11](=[N:20]/[C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[C:23]=2[F:32])/[S:10]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)CCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cccc(C(F)(F)F)c1F
Reactant: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To the suspension of cerium(III) chloride (86 mg, 0.35 mmol) in THF (3 mL) was added the product from Example 77 (100 mg, 0.23 mmol) in THF (0.5 mL). The mixture was stirred at rt for 1 hr. The above mixture was cooled to −40° C. and methylmagnesium bromide (41.6 mg, 0.348 mmol) was added dropwise. The reaction was stirred for 40 min at −40° C., quenched with saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 57 mg (55%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.23 (s, 6 H) 1.57-1.61 (m, 2 H) 1.68 (s, 9 H) 1.74 (s, 1 H) 1.81-1.89 (m, 2 H) 2.88 (t, J=7.63 Hz, 2 H) 7.30 (t, J=7.93 Hz, 1 H) 7.69 (t, J=6.41 Hz, 1 H) 8.01-8.04 (m, 1 H) 8.39 (td, J=7.93, 1.53 Hz, 1 H); MS (DCI/NH4+) m/z 447 (M+H)+.