Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-piperidone ethylene ketal (1.43 g, 10 mimol) and triethylamine (10 mmol, 1.4 ml) was added dropwise a solution of 4-methylbenzoyl chloride (1.55 g, 10 mmol) in ethyl acetate (20 ml) and the mixture stirred for 2 h. The mixture was washed twice with water followed by brine, dried over sodium sulphate and evaporated to give an off-white solid, m.p. 59°-61° C.
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>C(#N)C>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([N:3]=[C:2]2[NH:21][CH2:20][CH2:19][CH2:18][NH:17]2)=[CH:9][CH:8]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: ClC(Cl)=Nc1ccc(C2CCCCC2)cc1
Reactant: NCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCc1ccc(N=C2NCCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 g of N-dichloromethylene 4-cyclohexylaniline in 40 ml of acetonitrile is added dropwise to a solution of 1 ml of 1,3-diaminopropane in 20 ml of acetonitrile in 15 minutes at room temperature. After the addition of 1 ml of triethylamine, the solution is stirred for 1 hour at room temperature, after which the reaction mixture is filtered while warm. After distilling off the solvent the residue is taken up in ether and successively washed with 2 N sodium hydroxide solution and water. The ether layer is dried and evaporated, after which the residue is recrystallized from acetonitrile. The resulting 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine has a melting point of 180°-182° C. 2-(4-n-hexylphenyl)imino-hexahydropyrimidine was prepared in a corresponding manner.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([F:13])([F:12])[C:9]([F:15])([F:14])[C:8]=2[CH:16]=1)([O-])=O>CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([F:12])([F:13])[C:9]([F:15])([F:14])[C:8]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(F)(F)C(F)(F)O2
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc2c(c1)C(F)(F)C(F)(F)O2
Yield: 94.4 %

Procedure:
Hydrogenation of 2.15 g (0.011 mole) of 5-nitro-2,2,3,3-tetrafluorobenzofuran (prepared as in Example 1, Part A) with a catalytic amount (0.25 g) of platinum oxide in 150 ml of methanol produced 2.15 g of 5-amino-2,2,3,3-tetrafluorobenzofuran.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([NH:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[N:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])=[O:17])[CH2:14][CH2:15]2)[N:5]=1
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reactant: Nc1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Nc2ccncc2)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (75 mg, 0.18 mmol, 1.0 equiv) and diisopropylethylamine (DIEA, 154 □l, 0.875 mmol, 5.00 equiv) in acetonitrile (3 ml) at room temperature, 4-aminopyridine (43.0 mg, 0.349 mmol, 2.00 equiv) was added. The reaction mixture was heated to 65° C. and stirring was continued overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved up in 1.5 ml DMSO and purified via reverse-phase HPLC purification to afford the title compound. MS (ES+): m/e 487.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].FC(F)(F)C(O)=O.C(Cl)Cl>C([SiH](CC)CC)C>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(O)c3ccccc3C(F)(F)F)sc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
5-Bromo-6-{hydroxy[2-(trifluoromethyl)phenyl]methyl}-1-isobutyl-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (33.47 g) was dissolved in triethyl silane (100 mls) and cooled to 0° C. before trifluoroacetic acid (100 mls) was added dropwise. After complete addition the resultant thick suspension was diluted by the addition of DCM (100 mls) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and partitioned between DCM and 50% aqueous sodium hydrogen carbonate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The resultant off white solid was stirred vigorously with isohexane for 1 hour before being collected by filtration to yield 27.286 g (84.5%) of the subtitle compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:9]2[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:26][C:27]=1[O:32][CH3:33]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: COc1cc(CBr)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2ccc(F)c(OC)c2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.50 g) in DME (12.0 mL) were added 4-(bromomethyl)-1-fluoro-2-methoxybenzene (0.39 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.07 g) and 2 mol/L aqueous sodium carbonate solution (1.63 mL), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, and diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.45 g).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1.[CH:22](O)([CH3:24])[CH3:23]>ClCCl.C(=O)(O)[O-].[Na+].O>[CH:22]([O:20][C:19](=[O:21])[C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][N:16]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CC(C)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(Cl)ccn1
Reaction time: 1 h
Yield: 87 %

Procedure:
N,N-Dimethylformamide (0.3 mL) was added dropwise to a suspension of oxalyl chloride (6.6 mL, 76 mmol) and 4-chloropicolinic acid (10.0 g, 63.5 mmol) in dichloromethane (200 mL). The reaction mixture was stirred for 1 hour and additional oxalyl chloride (4 mL) and N,N-dimethylformamide (0.2 mL) was added. After a further 30 minutes, isopropanol (100 mL) was slowly added, followed by, after a further 15 minutes, solid sodium bicarbonate (12 g). The reaction mixture was diluted with 1:1 saturated sodium bicarbonate solution and water, the aqueous phase extracted with dichloromethane (3×100 mL), and solvent removed from the extract under reduced pressure. The residue was purified by by flash chromatography (rf: 0.48 in 2:1 hexanes:ethyl acetate) to give 4-chloropicolinic acid isopropyl ester (11.0 g, 87% yield). 200.1 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[O:10][CH2:11][CH2:12][N:13]([C:17](=O)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[O:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)N2CCOc3ccc(-n4ccnc4)cc3OCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)Nc1ccc(CCN2CCOc3ccc(-n4ccnc4)cc3OCC2)cc1

Procedure:
In a manner similar to example 8, react 9-(1H-imidazol-1-yl)-4-[2-[4-[(methylsulfonyl)amino]phenyl]acetyl]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O:20][C:21]1[CH:22]=[C:23]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:24][CH2:25][CH2:26][CH:27]=[N:28][NH:29][C:30]([NH2:32])=[S:31])(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[CH2:1]([N:29]([C:30](=[NH:32])[SH:31])[N:28]=[CH:27][CH2:26][CH2:25][O:24][C:23]1[CH:33]=[C:34]([CH3:36])[CH:35]=[C:21]([O:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])(=[O:19])=[O:18])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NNC(N)=S)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCC=NN(Cc2ccccc2)C(=N)S)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A solution of benzyl bromide (15.5 μL, 0.13 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.5 mL) was added dropwise over 20 minutes to a mixture of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]-propionaldehyde thiosemicarbazone (55.3 mg, 0.13 mmol, as prepared in the preceding step) and sodium bicarbonate (28.8 mg, 0.34 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.5 mL). The reaction was stirred for 5 hours at ambient temperature, then additional benzyl bromide (15.5 μL, 0.13 mmol) in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The reaction was stirred overnight at ambient temperature then concentrated to remove solvents. The residue was triturated with dichloromethane and filtered through Celite. After concentration, crude product was purified by flash column chromatography through silica gel (1:1 diethyl ether/hexane) to give the title compound as an oil (42 mg, 1:4 mixture of isomers, 62%). 1H-NMR (300 MHz, CDCl3) δ 7.80-7.85 (m, 2H), 7.57-7.63 (m, 1H), 7.23-7.40 (m, 5H), 6.98-7.12 (m, 2H), 6.59 (br s, 1H), 6.52 (br s, 1H), 6.46 (t, 1H, J=2 Hz), 4.29 and 4.28 (s, 1H), 4.10 (t, 2H, J=6.5 Hz), 4.01 (s, 3H), 2.94 and 2.73 (q, 2H, J=6 Hz), 1.55 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H27N3O5S2 : 514.1 (M+H). Found: 513.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(COc2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a solution of 2-chloro-5-nitrophenol (10 g, 57.6 mmol) in acetonitrile (100 mL) was added potassium carbonate (11.7 g, 86 mmol) followed by 4-methoxy benzyl bromide (13.9 g, 69.1 mmol), at room temperature. The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. It was then filtered and the solid mass was washed with ethyl acetate (100 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica gel) using 2% MeOH in CHCl3 to give 1-chloro-2-(4-methoxybenzyloxy)-4-nitrobenzene (15 g, 89%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, s), 7.79 (1H, d, J=8.8 Hz), 7.53-7.51 (1H, d, J=8.4 Hz), 7.41-7.39 (2H, m), 6.95-6.87 (2H, m), 5.17 (2H, s), 3.82 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.O.[OH-].[Li+].O1CCCC1.C(O)C.O.O>ClCCl>[CH3:1][C:2]1([CH3:23])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1
Reactant: CCOC(=O)c1cnc2cc(OCC3COC(C)(C)O3)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2ccn3c(C(=O)O)cnc3c2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Ethyl 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.8 g, 5.63 mmol) and lithium hydroxide monohydrate (0.284 g, 6.75 mmol) were combined in a flask containing tetrahydrofuran/ethanol/water (1:2:1, 56 mL). After stirring overnight at ambient temperature, the solvent was removed under vacuum to give a yellow gum. Water (20 mL) and dichloromethane were added. The aqueous layer was separated and cooled in an ice-water bath before adjusting to pH 4 with 20% citric acid. A precipitate formed and was collected by filtration. The solids were washed with a small amount of water (5 mL) and dried under vacuum to give 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)c(C)c1
Reaction time: 3 h

Procedure:
2,4-Dimethylbenzoic acid (1.502 g, 10 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Alfa Aesar) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.963 mL, 11.00 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.639 g.
Reaction SMILES: [NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[OH:23])=[O:7])=[C:4]([O:27][CH3:28])[CH:3]=1.Cl.CC(O)C.N>C1COCC1>[NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([O:8][CH2:9][C@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[OH:23])=[O:7])=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cc(N)c(Cl)cc1C(=O)OC[C@H]1CCNC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A mixture of (±)-1,1-dimethylethyl cis-4-[[(4-amino-5-chloro-2-methoxybenzoyl)oxy]-methyl]-3-hydroxy-1-piperidinecarboxylate (0.053 mol) in THF (250 ml) and a mixture of HCl and 2-propanol (25 ml) was stirred for 2 hours at room temperature, then for 10 minutes at 50° C., then cooled again to room temperature. The mixture was alkalinized with NH3. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated, yielding 4.6 g (29%) (±) cis-(3-hydroxy-4-piperidinyl)methyl 4-amino-5-chloro-2-methoxybenzoate (interm. 6-a).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].[CH:17]([N:20](CC)C(C)C)([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CC(N)C>ClCCl>[CH:17]([NH:20][C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])=[O:11])([CH3:19])[CH3:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)N
Product: COC(=O)c1ccc(C(=O)NC(C)C)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a solution of 4-(methoxycarbonyl)-2-nitrobenzoic acid (0.50 g, 2.22 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (1.16 mL, 6.66 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.89 g, 2.33 mmol). The reaction mixture was stirred for 15 min. Propan-2-amine (0.20 mL, 2.33 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was then concentrated and the crude residue was purified by flash silica gel chromatography (30% to 60% EtOAc/hexanes) to afford methyl 4-[(isopropylamino)carbonyl]-3-nitrobenzoate (0.48 g, 80%). LC-MS: (FA) ES+ 268.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]2[CH:22]=[CH:21][O:20][C:19]=2[CH3:23])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][O:20][C:19]=3[CH3:23])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Cc1occc1COc1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1occc1COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
A mixture of (4-fluoro-phenyl)-boronic acid (300 mg, 2.1 mmoles), 3-(4-iodophenoxymethyl)-2-methyl-furan (123). (500 mg, 1.6 mmoles) and potassium acetate (0.6 g) in N,N-dimethylformamide (70 mL) was degassed, treated with [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (90 mg) and the mixture was agitated at 95° C. for 12 hours under an argon atmosphere. The mixture was concentrated in vacuo, partitioned between water (100 ml) and diethyl ether (200 ml). The aqueous phase was re-extracted with diethyl ether, and the combined ethereal phases were dried and evaporated. The residue was purified by flash chromatography, using diethyl ether as eluent, to afford compound 124 (200 mg) as a solid. This material was used directly.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1.[CH3:29][C:30]1(C)C(C)(C)OB(C=C)O1.C(N(CCCC)CCCC)CCC>CN(C)C=O.Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([CH:29]=[CH2:30])=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1Cl
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: C=Cc1nn(C2CCCCO2)c2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ncc12
Temperature: 95 °C
Reaction time: 15 h

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.2 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (44 μL, 0.26 mmol) (Aldrich Cat. No. 633348), tributylamine (54 μL, 0.22 mmol) and dichloro[bis(triphenylphosphoranyl)]palladium (5 mg, 0.007 mmol) in N,N-dimethylformamide (1 mL) in a reaction vial was degassed and sealed. The mixture was stirred at 95° C. for 15 h. After cooling it was equally split into two parts. The material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].O[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: OCCN1CCCC1
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)C(=O)C2c1ccccc1

Procedure:
The title compound, MS: m/e=582.2 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dione and 1-(2-hydroxyethyl)-pyrrolidine.
Reaction SMILES: N1C=CC=CC=1.[FH:7].N[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.N([O-])=O.[Na+].[OH-].[Na+]>CCCCCC>[F:7][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1
Reactant: F
Reactant: N#Cc1ccc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: N#Cc1ccc(F)cn1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To hydrogen fluoride-pyridine (100 ml) was added 5-amino-2-cyanopyridine (24.5 g, 0.206 mol) under ice cooling. The resulting mixture was stirred for 10 minutes. To the reaction mixture was added sodium nitrite (15.6 g, 0.226 mol). The resulting mixture was stirred at room temperature for 10 minutes, and then stirred at 50° C. for 2 hours. To the reaction mixture was added a 20% aqueous solution of sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic layer thus obtained was dried over sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (16.0 g, 0.131 mmol, 64%) as colorless needle crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl.Br[C:9]1[CH:14]=[CH:13][NH+:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)=[CH:10][CH:11]=1
Reactant: Brc1cc[nH+]cc1
Reactant: OC1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC1CCN(c2ccncc2)C1
Temperature: 150 °C

Procedure:
A mixture of 3-hydroxypyrrolidine (9.9 g, 113.64 mmol), 4-bromopyridinium hydrochloride (22.098 g, 113.64 mmol), triethylamine (47.5 mL, 341.0 mmol) and 3:1 ethanol:water (150 mL), in a pressure tube reaction vessel, was purged with nitrogen and sealed. The mixture was heated to 150° C. for 96 hours and cooled. The solvent was evaporated and ethyl acetate (50 mL) was added. After trituration, the organic solvent was decanted off and saved. Methylene chloride (80 mL) and 2 N sodium hydroxide (60 mL) were added to the solid. The mixture was shaken vigorously and was filtered with water and methylene chloride wash to give the title compound as an off-white solid. The organic supernatant and the methylene chloride and water washes were combined. This mixture was extracted with methylene chloride. The organic layer was sodium sulfate dried and concentrated. The residue was triturated with methylene chloride and the solid was filtered. This solid was combined with the solid from above and vacuum dried (100° C. at 133 Pa for 14 hours) to give the title compound as an off-white solid (8.52 g, 46%).