Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:29][CH2:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: CCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Intermediate 29 was coupled with propionaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 445.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH:9]1[OH:18])[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=[O:18])[CH2:15]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C3)C1O)C2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC3CC(CC(C3)C1=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 20B (500 mg, 1.87 mmol) in 10 mL of DCM was added Dess martin periodinane (1.03 g, 3 mmol) at one portion at rt. The mixture was stirred at rt overnight and was quenched by 20 mL of NH4Cl aq (Sat'd) solution. The mixture was extracted by DCM (5 mL×3) and the combined DCM layers were dried over Na2SO4. Solvent was remove under vacuum and the residue was purified by silica gel chromatography (Hexane:EtOAc 2:1(v/v)) to give the title compounds (20C) (510 mg, 90%). LC-MS (ESR): m/z=266 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 660.9 %

Procedure:
Under ice-cooling, a solution of 25.0 g (15.8 mmol) of 4-fluorobenzoyl chloride in 30 ml of ether was added dropwise to a mixture solution of 22.6 g (15.8 mmol) of 1-aminocyclohexanecarboxylic acid and 25.0 g (23.7 mmol) of sodium carbonate in 100 ml of ether and 300 ml of water, and the mixture was stirred at room temperature overnight. After the ether layer was separated, under ice-cooling, the aqueous layer was neutralized by concentrated hydrochloric acid, and the precipitated crystal was collected by filtration to obtain 27.7 g (66%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=C(C(O)=O)[C:3]=1[S:22][C:23]([F:26])([F:25])[F:24].[NH3:27].[O:28]1[CH2:33][CH2:32]OCC1>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:32]([C:33]([NH2:27])=[O:28])[C:3]=1[S:22][C:23]([F:26])([F:25])[F:24]
Reactant: N
Reactant: Nc1c(SC(F)(F)F)c(C(=O)O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C1COCCO1
Solvent: O
Product: NC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthio-1H-pyrazole-3-carboxylic acid (1.00 g, 2.27 mmol) and 1,1-dicarbonylimidazole (0.45 g, 2.72 mmol) in dioxane was heated to 50° C. for 2 hours. An aqueous solution of ammonia (33%, 80 ml) was then added and stirring continued at 50° C. for 4 hours. The cooled mixture was diluted with water and extracted with ethyl acetate/heptane (1:1). The combined organic phase was washed with aqueous potassium hydrogensulfate (5%), dried over magnesium sulfate and evaporated to give the title compound (0.980 g, yield 98%) as a white foam, 1H NMR (CDCl3): 4.36 (bs, 2H, NH2), 5.60 and 6.69 (bs, 2H, C(O)NH2), and 7.82 (s, 2H, Ar—H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:4][C:3]=1[O:15][CH3:16].C([N:19]([CH2:22][CH3:23])CC)C.[C:24](Cl)(=[O:28])[O:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:22]([NH:19][C:12](=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:24]([O:25][CH2:26][CH3:27])=[O:28])=[C:3]([O:15][CH3:16])[CH:4]=1)/[CH:23]=[C:11](/[CH2:10][CH2:9][CH:8]=[C:5]([CH3:6])[CH3:4])\[CH3:12]
Reactant: COc1cc(C=CC=CC(=O)O)ccc1O
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(C=CC=CC(=O)NC/C=C(\C)CCC=C(C)C)cc1OC
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Separately, 2.33 g of 5-(4'-hydroxy-3'-methoxyphenyl)pentadienoic acid is suspended in 50 ml of methylene chloride under an argon atmosphere. To the suspension cooled to -10° C. are added 2.95 ml of triethylamine and 2.03 ml of ethyl chlorocarbonate. To the mixture, after stirred for 30 min., is added a suspension of the geranylamine-hydrazide mixture in methylene chloride. The resulting mixture is stirred at -10° C. to 0° C. for 4 hours. The reaction mixture is filtered, and precipitates are washed with methylene chloride. Combined filtrate and washing are washed successively with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 2.61 g of 5-(4'-ethoxycarbonyloxy-3'methoxyphenyl)pentadienoic acid geranylamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:21]1[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Yield: 100 %

Procedure:
The method of Example 1 was followed using 1-fluoro-2-nitrobenzene (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (2.0 eq) in EtOH at 55° C. for 72 hours yielding tert-butyl 4-(2-nitro phenyl)piperazine-1-carboxylate (100%). LCMS (m/z): 308.1 (MH+); LC Rt=3.25 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1.[CH3:12][N:13]([CH3:29])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[N:8]=[C:3]([CH2:2][NH:1][C:27]([NH:26][S:23]([C:18]2[C:17]([S:14]([N:13]([CH3:29])[CH3:12])(=[O:16])=[O:15])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])=[O:28])[N:4]=1
Reactant: COc1cc(C)nc(CN)n1
Reactant: CN(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1cc(C)nc(CNC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C)n1
Reaction time: 18 h
Yield: 49.9 %

Procedure:
The product from Example 9 (0.90 g) was added in a steady stream to a stirred solution of 2.3 g of 2-(N,N-dimethylsulfamoyl)benzenesulfonyl isocyanate in 20 ml dry methylene chloride at room temperature. The reaction solution was stirred for an additional 18 hours and the solvent was removed in vacuo. The resulting yellow foam was stirred with 1-chlorobutane for ca. one hour. The mixture was filtered and the collected solids dried to yield 1.3 g of N'-[(4-methoxy-6-methylpyrimidin-2-yl)methylaminocarbonyl]-N,N-dimethyl-1,2-benzenedisulfonamide, m.p. 153°-156° C., as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CN(C=O)C>[CH3:12][S:13]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a stirred solution of 4-nitrobenzyl bromide (10.0 g, 46.3 mmol) in DMF (25 mL) was added sodium methanesulfinate (7.1 g, 69.4 mmol). The reaction mixture was stirred at 65° C. for 30 minutes, and then partitioned between water (30 mL) and EtOAc (30 mL). The organic fraction was separated, washed with water (2×30 ml), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (7.5 g, 75%) as a yellow solid that was used without further purification. δH (DMSO-d6) 8.28 (2H, d, J 8.8 Hz), 7.70 (2H, d, J 8.8 Hz), 4.72 (2H, s), 2.97 (3H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:8][CH2:9][CH2:10][CH3:11]>C(OCC)C>[CH2:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CCNCC1
Reactant: CCCCI
Solvent: CCOCC
Product: CCCCN1CCCCC1

Procedure:
45.0 g piperidine (0.53 mol) was added to 150 g ethyl ether. 48.6 g iodobutane (0.26 mol) was then added drop wise. After 3 days the resulting piperidine hydroiodide salt was removed by filtration and the N-butylpiperidine was recovered from the ether solution.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:5]=1.[Li+].[OH-].O>O1CCOCC1>[O:21]=[C:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid methyl ester (D7) (201 mg, 0.666 mmol) in dioxane (2 ml) was treated with LiOH (42 mg, 0.998 mmol) and water (1 ml). The reaction mixture was stirred for 2 hours at room temperature. The solvent was then evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH=1. The product precipitated in the aqueous layer and was removed by filtration and dried in vacuo to D8 (128 mg) as white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[SH:75][CH2:76][CH2:77][C:78]([O:80][CH3:81])=[O:79]>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].O1CCOCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:7][C:2]=1[S:75][CH2:76][CH2:77][C:78]([O:80][CH3:81])=[O:79]
Reactant: COC(=O)CCS
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
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: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Temperature: 100 °C

Procedure:
A 25 mL round-bottomed flask is charged with N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (398 mg, 1.00 mmol), Pd2dba3 (22.1 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (27.9 mg, 0.048 mmol), N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.9 mmol), methyl 3-mercaptopropanoate (0.12 mL, 1.1 mmol), and dioxane (10 mL). The reaction mixture is heated at 100° C. under nitrogen for 2 hours, then cooled to room temperature, filtered and concentrated. The residue is purified via chromatography, eluting with 40% EtOAc in hexanes, to afford methyl 3-(4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=O)C.C1(=O)O[CH2:15][CH2:14][O:13]1.[O-]CC.[Na+].C([NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[Cl:36])(=O)C.N1C=CC=CC=1>C(O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:36][C:27]1[CH:28]=[C:29]([S:32]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([S:11][CH2:15][CH2:14][OH:13])=[CH:9][CH:10]=2)(=[O:34])=[O:33])[CH:30]=[CH:31][C:26]=1[NH2:25]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1OCCO1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: CC[O-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2ccc(SCCO)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A solution of 4-acetamidothiophenol (8.35 g, 50.0 mmol), ethylene carbonate (5.5 g, 62.5 mmol) and sodium ethoxide (4.1 g, 60.0 mmol) in ethanol (250 ml) was heated at reflux overnight and then cooled to ambient temperature and evaporated to dryness. The residue was dissolved in diethyl ether (500 ml), washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (120 ml) and 2M aqueous sodium hydroxide (60 ml) was added. The mixture was heated at reflux overnight and then cooled to ambient temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralised to pH 7 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness. The residue was dissolved in DCM (100 ml) and added to a solution of 4-acetamido-3-chlorobenzenesulphonyl chloride (5.5 g, 20.5 mmol), 4-dimethylaminopyridine (50 mg, 0.4 mmol) and pyridine (5.0 ml, 60 mmol) in DCM (100 ml). The mixture was stirred at ambient temperature overnight, the solution was evaporated to dryness, the residue dissolved in diethyl ether (450 ml), washed with 1M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2M aqueous sodium hydroxide (25 ml) was added. The mixture was heated at reflux overnight and then cooled to ambient temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralised to pH 7 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts were washed with brine, dried and evaporated to dryness. The residue was purified by column chromatography using 25% EtOAc in DCM to yield the title compound (630 mg, 1.8 mmol). NMR: 2.9 (t, 2H), 3.5 (m, 2H), 4.8 (t, 1H), 6.2 (s, 2H), 6.75 (d, 1H), 7.0 (d, 2H), 7.2 (d, 2H), 7.3 (dd, 1H), 7.45 (d, 1H); MS: 357.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[C:16]([F:21])[CH:15]=1>CN1CCCC1=O>[Br:13][C:14]1[CH:19]=[C:18]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:17]=[C:16]([F:21])[CH:15]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(F)cc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 2.2 ml of p-methoxybenzyl alcohol and 50 ml of N-methylpyrrolidone was added 840 mg of sodium hydride (60% oil dispersion), and the resulting mixture was stirred at room temperature for 45 minutes in a nitrogen atmosphere. To the reaction mixture was added 2 ml of 1-bromo-3,5-difluorobenzene, followed by stirring at 50° C. for 1.5 hours. The reaction mixture was poured into 50 ml of ice-diluted hydrochloric acid and extracted three times with diethyl ether-hexane (1:1 by volume. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a hexane-ethyl acetate (19:1 by volume) mixed solvent. The fraction containing the desired compound was concentrated to furnish 4.88 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5](Cl)=[O:6].CC[N:14](CC)CC.[OH-].[Na+]>C1COCC1>[C:5]([NH2:14])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride Compound 1e (0.25 mmol, 0.06 g) in THF (1 mL) was added dropwise over 2 min to a solution of Compound 2c (0.2 mmol, 0.05 g) and Et3N (0.4 mmol, 0.06 mL) in THF (4 mL) at 0° C. The resulting suspension was allowed to warm to r.t. overnight, then made basic with a 2N NaOH-solution and extracted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were washed with brine, then dried over Na2SO4 and filtered. The solvent was removed in vacuo to yield 3,4-dichloro-N-(4-{2-[methyl-(tetrahydro-pyran-4-yl)-amino]-ethyl)}-phenyl)-benzamide Compound 2d as a yellow solid. The product was purified by preparative TLC (10:1 EtOAc:MeOH) (0.06 g, 73%). MS m/e 407 (M+H, 100%);
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:8]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[C:7]1=[C:30]=[O:31])(=[O:4])=[O:3].CO.[H][H]>[Pd].O1CCCC1>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][NH:9][C@@H:8]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[C:7]1=[C:30]=[O:31])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O[C@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H](N2CCNC2=O)C1=C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@@H](N2CCNC2=O)C1=C=O
Yield: 82.1 %

Procedure:
A mixture of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)-carbonylpyrrolidine (30 g), 10% palladium on carbon (10 g), methanol (300 ml) and tetrahydrofuran (150 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(2-oxoimidazolidin-1-yl)-carbonylpyrrolidine (14.92 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[Pd].O>[ClH:15].[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CO)n2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1ccc(-c2nc(Cl)c(CO)n2Cc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 1-benzyl-4-chloro-5-(hydroxymethyl)-2-(4-nitrophenyl)imidazole (1.0 g, 2.8 mmol, Compound 8 from Example 5), 10% palladium on carbon (0.10 g), 12M HCl (1.0 ml) 96% ethanol (50 ml) and water (50 ml) was hydrogenated at 55 psi for 1.5 hours on a Parr shaker hydrogenation apparatus. The mixture was filtered through a celite pad and then through a fluted filter paper. Evaporation left 1.5 g of amber oil.
Reaction SMILES: [C:1](O)(=[O:3])C.[NH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1>C(O)=O>[CH:1]([NH:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)=[O:3]
Reactant: CCOC(=O)c1cn(N)c2nc(C)ccc2c1=O
Reactant: CC(=O)O
Solvent: O=CO
Product: CCOC(=O)c1cn(NC=O)c2nc(C)ccc2c1=O
Temperature: 0 °C

Procedure:
Formic acid (13 ml, 0.33 m) was added to 31.2 ml (0.33 m) of acetic acid stirred in an ice bath. The mixture was stirred 15 minutes at 0° C. and 15 minutes at 55° C. It was then recooled to 0° C. and 8.1 g (0.033 m) of ethyl 1-amino-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate was added. An additional 9.2 ml of formic acid was then added, and the reaction mixture was stirred one hour at 0° C. and two hours at room temperature. The reaction mixture was poured into ice-water, and the solid product collected by filtration, washed with water, tetrahydrofuran and ether, and dried at 75° C. in vacuo to give 4.4 g of ethyl 1-(formylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 214° C. (decompn), which contained a minor amount of the corresponding N,N-diformyl compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].C=O.[BH3-][C:43]#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:29][CH2:30][N:31]([CH3:43])[CH2:32][CH2:33]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCN(C)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a stirred solution N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in methanol was added formalin (5 equiv.) stirred it at room temperature for 10 min. Then NaBH3CN (1 equiv.) was added to it Resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (29% yield). LCMS: 546.30 (M+1)+; HPLC: 99.94% (@ 254 nm) (Rt; 5.067); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (bs, 1H), 8.83 (bs, 1H), 8.30 (s, 1H), 7.83 (d, 1H, J=13.20 Hz), 6.90 (bs, 1H), 5.89 (s, 1H), 5.25-5.15 (m, 1H), 4.38 (d, 2H, J=3.6 Hz), 4.31 (bs, 1H), 4.20 (bs, 1H), 3.71 (bs, 2H), 2.77 (bs, 3H), 2.65 (bs, 2H), 2.20 (s, 3H), 2.14 (s, 3H), 2.12 (s, 3H), 1.91 (bs, 2H), 1.60 (bs, 4H), 1.50 (d, 6H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1C(C#N)=C(N2CCC(C3N(CCNC)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:35][NH:36][CH3:37])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=507, obsd.=507).