Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[CH:34]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2C(=O)C3C=CC=CC=3C2=O)[CH2:6][CH2:5]1.O.NN.Cl>CO>[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]3[S:32][C:31]([CH3:33])=[N:30][C:29]=3[CH:34]=2)[CH2:5][CH2:6]1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)ccc2s1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCN)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-(2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azoline-1,3-dione (101 mg, 0.21 mmol) in MeOH (0.84 mL) was treated with hydrazine hydrate (0.07 mL) and stirred at RT for 14 hours. HCl (1 mL, conc) was added and the solution was heated to 88° C. for 14 hours. Upon cooling, the resulting solid was filtered off and washed with H2O and EtOAc. The filtrate was pH adjusted to >12 (NaOH) and extracted with EtOAc. The combined organic layers were then concentrated to afford (2R)-1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol as an oil.
Reaction SMILES: [C:1]1([C@@H:11]([NH:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:19]=[O:20]>C(O)CCC>[C:1]1([C@@H:11]([N:13]([CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[CH2:19][O:20][CH2:10][CH2:1][CH2:2][CH3:3])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: C[C@H](NC[Si](C)(C)C)c1cccc2ccccc12
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@@H](C)c1cccc2ccccc12

Procedure:
The title compound was prepared from (S)-(-)-N-1-(1-naphthyl)ethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (80% pure) as a pale yellow oil (5.5 g, 82%)δH [CD3)2CO] 0.1 (s, SiMe3), 0.93 (t, J 7 Hz, CH3CH2), 1.2-1.7 (m, CH3CH and (CH2)2), 2.22, 2.45 (AB quartet, J 15 Hz, NCH2Si), 3.25 (t, J 7 Hz, CH2O), 4.22, 4.35 (AB quartet, J 10 Hz, NCH2O), 4.78 (q, J 7 Hz, CH), 7.3-8.5 (m, naphthyl).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](O)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].CN(C)C=O.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([Cl:30])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 2 h

Procedure:
3.37 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid are suspended in 100 ml of toluene; 0.1 ml of dimethylformamide and 1.64 g of thionyl chloride are added and the whole is heated to 80°, stirred for 2 hours at 80°-90° and concentrated to dryness by evaporation under reduced pressure. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid chloride is obtained which can be used without being further treated.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([F:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH3:21]>C1COCC1>[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:21])=[O:16])=[C:13]([F:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: N
Reactant: CC(C)(C)c1ccc(C(=O)O)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(N)=O)c(F)c1
Reaction time: 1 h

Procedure:
Oxalyl chloride was added to a THF solution of 4-tert-butyl-2-fluorobenzoic acid and stirred for 1 hour, and aqueous ammonia was added to this. By post-treating the reaction liquid, 4-tert-butyl-2-fluorobenzamide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C@@H:11]2[C@@H:15](OS(C)(=O)=O)[CH2:14][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12]2)=[CH:5][CH:4]=1.[N-:42]=[N+:43]=[N-:44].[Na+].O>CS(C)=O>[N:42]([C@H:15]1[C@@H:11]([O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:12][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2OS(C)(=O)=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 92.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (4.0 g, 6.85 mmol) in anhydrous DMSO (70 mL) was added sodium azide (1.78 g, 27.4 mmol). The resulting mixture was heated at 100° C. for 18 hours. The solution was cooled to ambient temperature, poured into water (150 mL) and the solid which separated was collected by filtration and washed with water and dried to afford (3R,4S)-tert-butyl 3-azido-4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine-1-carboxylate (3.37 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[N:6][CH:7]=1
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.2 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.498 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-5-fluoropyrimidine (0.194 ml, 1.573 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (732 mg, 2.247 mmol), Xantphos™ (65.0 mg, 0.112 mmol), and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.037 mmol) and then heated at reflux for ˜3 hrs. The mixture was cooled to room temperature, diluted with water (˜25 ml) and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with water and then with brine and evaporated to give a yellow/brown residue. This was purified by automated silica-gel column chromatography (Biotage SP-4), eluting with a 0-100% gradient of ethyl acetate in isohexane (8 column volumes), to give 1,1-dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 52.3% yield) as a white solid. (ii) 1,1-Dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 0.783 mmol) was dissolved in a mixture of trifluoroacetic acid (2 ml, 26.0 mmol) and dichloromethane (4 ml) at 0° C. and then left to warm to room temperature and stirred overnight. The mixture was evaporated (azeotroping with toluene and then with dichloromethane to remove all TFA traces) to give 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (211 mg) as a white solid which was used without further purification in subsequent chemistry. LC/MS MH+=240.85.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][OH:27])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C(Cl)Cl.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[CH3:40][S:41]([O:27][CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:16][CH2:17][N:12]1[C:9]1[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:28])[F:29])=[CH:7][CH:8]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CO)cc1)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
A 1-L round-bottomed flask was charged with 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (42.7 g, 95 mmol), 200 mL of CH2Cl2, and triethylamine (15.18 mL, 109 mmol). After cooling to 0° C., methanesulfonyl chloride (7.75 g, 99 mmol) was added. After 5 min, another 1 equiv of triethylamine and methanesulfonyl chloride were added. The mixture was then diluted with water and extracted with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated. Purification by column chromatography on silica gel (0 to 50% EtOAc in hexanes) gave ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (35.0 g) as a light-yellow brittle foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18]([C@@H:20](/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:39])=[O:38])[C@@:21]([OH:28])([CH2:25][CH2:26]C)[C:22]([OH:24])=[O:23])=[O:19])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1C=CC(C[C@H](NC([C@@H](/C=C/CCCCCCC(F)([F:91])CCCCCCC)[C@@](O)(CCC)C(O)=O)=O)C(O)=O)=CC=1)C#CC>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18]([C@@H:20](/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:39])=[O:38])[C@:21]([CH2:25][CH2:26][F:91])([OH:28])[C:22]([OH:24])=[O:23])=[O:19])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)O)[C@@](O)(CCC)C(=O)O
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)O)cc1
Product: CCCCCCCS(=O)(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)O)[C@@](O)(CCF)C(=O)O

Procedure:
(E)-(2S,3S)-3-[(S)-2-(4-Butoxy-phenyl)-1-carboxy-ethylcarbamoyl]-11-(heptane-1-sulfonyl)-2-hydroxy-2-propyl-undec-4-enoic acid (No. 5527300) was synthesized by the synthetic method of (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-carboxy-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-propyl-nonadec-4-enoic acid (No. 5501825), using (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2-fluoro-ethyl)-11-(heptane-1-sulfonyl)-2-hydroxy-2-undec-4-enoic acid (No. 5514421) as a starting material.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[CH2:10][C@@H:5]1[C:6]2([CH3:12])[CH3:11].C([Li])CCC.[CH:18](OCC)=[O:19]>C1COCC1>[CH3:1][O:2][N:3]=[C:4]1[C@@H:9]([CH:18]=[O:19])[CH2:8][C@H:7]2[CH2:10][C@@H:5]1[C:6]2([CH3:12])[CH3:11]
Reactant: CON=C1CC[C@H]2C[C@@H]1C2(C)C
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CON=C1[C@@H](C=O)C[C@H]2C[C@@H]1C2(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cold (−78° C.) solution of (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime, 77a, (1.27 g, 7.59 mmol) in THF (33 mL) was added dropwise a solution of n-butyllithium (3.34 mL of 2.5 M solution in hexanes, 8.35 mmol). After stirring the mixture 20 min at −78° C. ethyl formate (0.61 mL, 7.59 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 3 hours and then quenched by pouring into aqueous saturated NaHCO3 solution. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 810 mg yellow oil: LCMS RT=3.54 (M+H) 196.28.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][C@H:27]4[CH2:32][CH2:31][C@@H:30]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:28]4)[CH:22]=3)[CH:17]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[I:38]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][C@H:27]4[CH2:32][CH2:31][C@@H:30]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:28]4)[C:22]=3[I:38])[CH:17]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc(C4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)ccc3c2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc(C4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)ccc3c2I)CC1
Reaction time: 0.08 h

Procedure:
A solution of {5-[6-(cis-4-butylcyclohexyloxy)-naphthalen-2-yl]-2,2-dimethyl-1,3-dioxinan-5-yl}-carbamic acid tert-butyl ester (0.101 g, 0.000197 mol) and N-iodosuccinimide (56 mg, 0.00025 mol, Acros) in methylene chloride (3.0 mL, 0.047 mol, Acros) was stirred at room temperature under an atmosphere of Argon. To this was added zirconium tetrachloride (14 mg, 0.000060 mol, Strem). After 5 min, the reaction mixture was evaporated then diluted with methylene chloride, silica gel was added and the solvent was evaporated. The material was purified by silica gel chromatography to give the product in 111 mg yield (88%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[NH2:26])=[CH:15][CH:14]=1>C(O)C>[CH3:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[C:20]2/[CH:21]([N:26]3[CH2:4][CH2:3][CH2:2]3)[CH2:22][CH2:23][CH2:24][CH2:25]/2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(C=C2CCCCC2N)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(/C=C2\CCCCC2N2CCC2)cc1

Procedure:
A mixture of N-[2-[4-methylphenyl)methylene]cyclohexyl]amine, from step C above, 0.64 g (3.2 mmol) with 1.28 g (6.4 mmol) of 1,3-dibromopropane and 0.88 g (6.4 mmol) of potassium carbonate in 20 ml of ethanol as refluxed 18 hr, evaporated and the residue was taken up in a water/diethyl ether mixture. The aqueous layer was separated and saturated with solid potassium hydroxide and extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. The residue, 0.67 g, was chromatographed using a HPLC Merck C silica gel column using a 3% methanol in chloroform solution containing 0.5% ammonium hydroxide mixture as eluent. Elution with 620 ml of this eluting mixture gave mixtures of products containing the N-allyl derivative of the starting N-[2-[(4-methylphenyl)methylene]cyclohexyl]amine. Elution of the column contents with 5% methanol in chloroform containing 0.5% ammonium hydroxide (240 ml) gave no product. The next 540 ml gave 180 mg of (±)-(E)-1-[2-[(4-methylphenyl)methylene]cyclohexyl]-azetidine. GC analyses (3% SE 30) 100% at 4.99 min, UV λmax(ε)247(15,300). HR mass spectrum Found 241.1844, Calcd. for C17H23N 241.1830. The NMR spectrum was also consistent for this named product.
Reaction SMILES: [C:1]([C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:33]I.[Cl-].[Na+]>CN(C)C=O>[CH3:33][N:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:7]3[CH2:6][CH2:5][C:4]([C:1](=[O:3])[CH3:2])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:9][CH2:8]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24]
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCOc2ccc3c(c2)CCC(=O)N3)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CCCOc2ccc3c(c2)CCC(=O)N3C)CC1
Reaction time: 1 h

Procedure:
2.0 Grams of 6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril and 0.25 g of sodium hydride (50% in oil) were mixed in 30 ml of dimethylformamide and stirred for 1 hour, then 0.7 g of methyl iodide was added thereto and stirred at a room temperature for 12 hours. The reaction mixture was poured into 80 ml of saturated sodium chloride solution and the organic layer was extracted with chloroform and the chloroform layer was washed with water and dried. Then the chloroform was removed by distillation and the residue was crystallized with hexane. The crude crystals were recrystallized from ligroin to obtain 1.7 g of 1-methyl-6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril as in the form of colorless needle-like crystals. Melting point: 115°-117° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=3[N+:24]([O-])=O)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1>[Ni]>[NH2:24][C:16]1[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)(=[O:13])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c([N+](=O)[O-])c1
Agent: [Ni]
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(N)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,4-dinitrobenzenesulfonamide (0.43 g, 1.14 mmol) was added Raney-Ni (100 mg), following by degas and replacement of air with H2. The reaction mixture was hydrogenated at room temperature for 2 hours. Once the reaction was completed (LC/MS), the mixture was filtered through Celite®. The filtrate was concentrated in vacuo to give a gummy material. The crude product was recrystallized in MeOH to give the title compound as an off-white solid (0.32 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.15 (s, 1H), 7.41 (s, 1H), 7.10˜7.18 (m, 3H), 5.72˜5.73 (m, 2H), 5.60 (s, 1H), 5.52 (s, 2H), 4.84 (s, 2H); MS (ESI) m/z=318 (M−1, negative); HPLC purity: 99.6% (MaxPlot 200-400 nm), 99.3% (220 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:27])[C:9]1[N:10]([CH2:24][CH2:25][OH:26])[CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[O:15]CC1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:27])[C:9]1[N:10]([CH2:24][CH2:25][OH:26])[CH:11]=[CH:12][C:13](=[O:23])[C:14]=1[OH:15]
Reactant: O=c1ccn(CCO)c(C(O)c2ccccc2F)c1OCc1ccccc1
Solvent: CCO
Product: O=c1ccn(CCO)c(C(O)c2ccccc2F)c1O

Procedure:
Hydrogenation of 1.5 g of 2-[(2-fluorophenyl)-hydroxy-methyl]-3-benzyloxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one analogously to Example 1and recrystallisation from ethanol yield 2-[(2-fluorophenyl)-hydroxy-methyl]-3-hydroxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one in the form of colourless crystals. M.p.: 177°-178° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[N:6]=[N+:7]([O-:21])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([N:18]([CH3:20])[CH3:19])[CH2:15]3)=[CH:11][C:9]=2[N:10]=1>COCCOC>[CH2:1]([NH:3][C:5]1[N:6]=[N+:7]([O-:21])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([N:18]([CH3:19])[CH3:20])[CH2:15]3)=[CH:11][C:9]=2[N:10]=1)[CH3:2]
Reactant: CN(C)C1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Reactant: CCN
Solvent: COCCOC
Product: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Yield: 82.5 %

Procedure:
Aqueous ethylamine (70%, 0.35 mL, 4.4 mmol) was added to a stirred solution of chloride 112 (240 mg, 0.9 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 113 (203 mg, 84%) as a yellow solid: mp (MeOH/EtOAc) 187-190° C.; 1H NMR δ 8.05 (s, 1H, H-9), 7.37 (s, 1H, H-5), 5.14 (br s, 1H, NH), 3.54 (dq, J=7.2, 1.3 Hz, 2H, CH2N), 3.06-3.21 (m, 3H, CH, CH2), 2.89-2.99 (m, 2H, CH2), 2.32 [s, 6H, N(CH3)2], 1.28 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 158.7, 152.1, 148.9, 140.9, 130.0, 120.8, 115.0, 67.7, 43.9 (2), 38.0, 37.1, 36.3, 14.8. Anal. calcd for C14H19N5O: C, 61.5; H, 7.0; N, 25.6. Found: C, 61.3; H, 7.1; N, 25.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][NH:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][N:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[CH2:31][NH:32]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(#N)C.O.[OH-].[Na+]>[NH2:32][CH2:31][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][NH:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][N:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cnc2c(NCc3nnc4ccc(-c5ccc(CNC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(CN)c(Cl)c5)nn34)ccnc2c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl (2-chloro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate (70 mg, 128 μmol) in DCM (2 mL) was added TFA (2 mL). Reaction solution stirred for 30 min at 23° C. Solvents then removed under reduced pressure and residue purified on prep-HPLC using a water/ACN (0.1% TFA) gradient. Resulting solid was dissolved in 1:1 ACN/water (1 mL) and pH adjusted to 10 with 1M NaOH (approx 10 drops). Resulting solid collected by filtration and washed with water (5 mL). MS (ESI pos. ion) m/z: 447 (MH+). Calc'd exact mass for C22H19ClN8O: 446.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([OH:11])=[N:7][NH:8][C:9]=1[CH3:10].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:35][O:34][C:32]([CH2:31][O:11][C:6]1[C:5]([O:4][C:3]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:2]=2[Cl:1])=[C:9]([CH3:10])[NH:8][N:7]=1)=[O:33]
Reactant: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1n[nH]c(C)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To a solution of 0.21 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 1.0 ml of N,N-dimethylformamide were added 0.10 g of methyl bromoacetate and 0.20 g of potassium carbonate, and the mixture was stirred for 3 hours at room temperature. Dilute hydrochloric acid was poured into this reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate. This solution was subjected to silica gel column chromatography to obtain 0.06 g of 3-(methoxycarbonyl)methoxy-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [present compound 5-17].
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C[O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21][CH3:22])=O>CCCCCCC>[CH3:22][O:21][CH2:19][CH2:18][O:17][CH2:16][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:14]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: COCCOCC(=O)OC
Solvent: CCCCCCC
Product: COCCOCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1

Procedure:
34.4 grams of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 29.6 grams of methyl 2-methoxyethoxyacetate and 300 mL of heptane are transferred to a 500 mL 3-necked, round-bottomed flask equipped with a mechanical stirrer, Dean-Stark trap and condenser. Trace amounts of water are removed by azeotropic distillation. 0.25 mL of tetraisopropyl orthotitanate is added to the reaction mixture. The reaction mixture is refluxed for six hours and the liberated methanol is collected in the Dean-Stark trap. The reaction mixture is allowed to cool and is then partitioned between 300 mL of ethyl acetate and 300 mL of water. The phases are separated and the organic phase is washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent leaves the title compound as a red oil.