Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][N:14]=[C:15]([C:21](=[O:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:9][CH2:10][CH2:11][O:13][N:14]=[C:15]([C:21](=[O:23])[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C(OCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
2-Bromoethyl benzoate (27.5 g.) was added dropwise to a stirred mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (15.7 g.), potassium carbonate (20.7 g.) and N,N-dimethylformamide (25 ml.) under ice cooling over 10 minutes, and stirred at ambient temperature for 4 hours. The resultant mixture was filtered and washed with acetone. The filtrate and washings were combined and concentrated in vacuo. After adding water (100 ml.) to the residue, the solution was extracted with methylene chloride three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:23][CH2:22][CH2:21][C:19]1[N:20]=[C:16]([NH:15][C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:17][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1

Procedure:
A mixture of 2-(2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)ethyl)isoindoline-1,3-dione (13.8 g, 30.2 mmol) and hydrazine hydrate (3.03 g, 60.5 mmol) in methanol (150 mL) was heated at reflux for 3 hours, then cooled and concentrated. The crude residue was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.N1CCCC1>CO>[Cl:1][C:2]1[C:3]2[C:10](=[CH:17][C:13]3[S:12][CH:16]=[CH:15][N:14]=3)[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: O=Cc1nccs1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2ncnc(Cl)c2C1=Cc1nccs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
Combine 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.3 g; 0.0017 mol), thiazole-2-carbaldehyde (0.23 mL, 0.0026 mol) in methanol (1.5 mL). Add drop-wise pyrrolidine (0.073 mL; 0.0008 mol). Stir at RT for 15 min. Filter the solids to give the title compound (0.35 g; 76.08%).
Reaction SMILES: [C:1]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[H][H]>[Pd].O>[C:1]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCCC=CCCCCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCCCCCCCCCCCCC1

Procedure:
100 kg of 8-cyclohexadecenone (odoriferously good quality: GC ratio of (E) and (Z) isomers was 2.5:1), 45 kg of acetone and 100 g of palladium on activated charcoal (Pd content: 5 wt. %) with 40% water content were placed in a stirred autoclave equipped with a gassing stirrer. The reaction mixture was hydrogenated for 12 hours at 35° to 40° C. and at 15 bar hydrogen pressure and then filtered. After removing the acetone 99.2 kg of cyclohexadecanone were obtained (GC content of cyclohexadecanone: >98%). The product thereby obtained was of a good perfumery quality. The perfumery quality could be improved still further by recrystallisation from methanol.
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[O:40]>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3F)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 21, step 3) was reacted with sodium iodide and 2-fluorophenylisocyanate to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:13][O:12][C:9]([C@@H:5]1[C:6](=[O:8])[NH:7][C@@H:4]1[CH2:3][C:2]([OH:16])=[O:1])([CH3:11])[CH3:10]
Reactant: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Reaction time: 0.67 h

Procedure:
A solution of (3R, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (250 mg) in acetone (26.7 ml) as added to a solution of 2N Jones reagent (2.67 ml) in acetone (24.03 ml) at ambient temperature over a period of 40 minutes and the mixture was stirred for another 40 minutes. After addition of an excess of isopropyl alcohol to the mixture, the solvent was distilled off. The residue was dissolved in chloroform and washed with a saturated aqueous sodium chloride. The aqueous layer was extracted four times with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The crystalline residue was washed with hexane to give 2-[(2R, 3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (211 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Br[CH2:31][CH2:32][O:33][CH3:34]>CN(C=O)C>[CH3:34][O:33][CH2:32][CH2:31][NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:26][C:19]3([CH3:25])[CH2:18][CH:17]2[CH2:23][C:21]([CH3:22])([CH3:24])[CH2:20]3)=[O:15])=[CH:12][CH:13]=1
Reactant: COCCBr
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (0.5 g, 1.34 mmol) in dry DMF (25 ml) was added sodium hydride (75 mg, 1.88 mmol in 60% mineral oil) and the mixture was stirred for 30 min. 1-Bromo-2-methoxy-ethane (224 mg, 1.61 mmol) was added and the mixture was heated to reflux and allowed to cool to room temperature with stirring. The reaction was quenched by addition of water (20 ml) and extracted with diethyl ether (2×25 ml). The combined organic phases were washed with saturated aqueous ammonium chloride (25 ml), dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (15 ml) and TFA (10 ml) was added. The resulting mixture was stirred for 5 hrs. at room temperature and evaporated in vacuo. To the residue was added water (10 ml) and diethyl ether (20 ml) and the pH was adjusted to 9 by addition of 1 N sodium hydroxide. The organic phase was separated and dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using EtOAc/heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording 0.3 g (68%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[C:20]([OH:25])[CH:19]=1>>[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[C:20]([O:25][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[Cl:13])[CH:19]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 2 step (iii) but instead using the product from example 3 step (i) and methyl(3,5-dihydroxyphenyl)acetate.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:44]=[CH:43][C:14]([C:15]([N:17]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:16])=[CH:13][CH:12]=1)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:15](=[O:16])[C:14]3[CH:43]=[CH:44][C:11]([CH2:10][NH:8][CH3:6])=[CH:12][CH:13]=3)[CH2:29][CH2:30]2)=[O:42])=[CH:36][CH:37]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)cc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
4-(N-tert-Butoxycarbonyl-N-methylamino)methyl-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (144 mg, 0.239 mmol) was dissolved in methylene chloride (4 ml) to which was subsequently added dropwise trifluoroacetic acid (0.4 ml) while cooling in an ice bath. After 2 hours of stirring at the same temperature, the solvent was removed by evaporation, and the resulting residue was diluted with methylene chloride (10 ml), washed with saturated sodium bicarbonate aqueous solution and saturated brine, and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation to obtain 119 mg (98.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)=[O:5])=[O:20])[CH3:23]
Reactant: COC(=O)COc1ccc(C(=O)CN)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCC(=O)c1ccc(OCC(=O)OC)cc1
Yield: 79.5 %

Procedure:
Pyridine (40ml.) was added to a stirred mixture of methyl 4-(aminoacetyl)phenoxyacetate hydrochloride (5.2g.) and ethyl chloroformate (2.3g.). An exothermic reaction occurred and was allowed to continue until a homogeneous solution was obtained. This solution was then cooled and the solid residue which formed was first separated, and then washed successively with ether (2 × 30ml.), water (2 × 30ml.) and ether (2 × 30ml.), before recrystallisation from toluene to give methyl 4-[N-(ethoxycarbonyl)aminoacetyl]-phenoxyacetate (4.7g.), m.p. 128°-129° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][N:12]2[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]2=[O:20])=[CH:7][C:6]=1[S:21]([NH2:24])(=[O:23])=[O:22])[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([NH:36][C:37](=O)[O:38]C2C=CC=CC=2)[N:29]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:18][C:15]1[C:16](=[O:17])[N:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])=[C:6]([S:21]([NH:24][C:37]([NH:36][C:30]3[N:29]=[C:28]([O:27][CH3:26])[CH:33]=[C:32]([O:34][CH3:35])[N:31]=3)=[O:38])(=[O:23])=[O:22])[CH:7]=2)[C:13](=[O:20])[C:14]=1[CH3:19]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOC(=O)c1ccc(NN2C(=O)C(C)=C(C)C2=O)cc1S(N)(=O)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(NN2C(=O)C(C)=C(C)C2=O)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 158 mg (0.43 mmol) of ethyl -2-(aminosulfonyl)-4-[(2,5-dihydro-3,4-dimethyl-2,5-dioxo-1H-pyrrol-1-yl)amino]benzoate and 118 mg (0.43 mmol) of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 73 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 15 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 20 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using dichloromethane as an eluent, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). Yield: 162 mg (58%). Melting point: 121°-123 ° C. (decomposed). Its physicochemical properties are shown in Table 4.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Reactant: Brc1ccnc(C2CC2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
Under an atmosphere of argon, tert-butyllithium (1.7 M in pentane) (0.576 mL, 0.98 mmol) was added dropwise to anhydrous tetrahydrofuran (4.00 mL) at −100° C. 4-Bromo-2-cyclopropylpyridine (0.097 g, 0.49 mmol) in anhydrous THF (2.00 mL) was added dropwise to the mixture. The solution was stirred for 2 minutes before dropwise addition of a solution of N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.200 g, 0.49 mmol) in anhydrous THF (2.00 mL). The reaction was stirred at −100° C. for 20 minutes, then the temperature was raised to −78° C. over a period of 10 minutes. The reaction was stirred at −78° C. for another 60 minutes. MeOH (2.0 mL) was added dropwise at −78° C. followed by hydrogen chloride (1.25 M in methanol) (1.176 mL, 1.47 mmol). The cooling bath was removed and the reaction was left to stir at ambient temperature for 60 minutes. The solvents were evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (×2), the organics were combined, dried (Na2SO4), filtered and evaporated. Purification by silica chromatography using 0 to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound (0.094 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH2:15])[CH2:9]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1C[C@@H](N)C[C@@H](F)C1

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-bisfluorophenyl)thiazole-4-carboxylic acid. Obtained the desired product as a white solid (50 mg). 1H NMR (500 MHz, DMSO) δ 9.25 (s, 1H), 8.18 (t, J=20.9 Hz, 1H), 7.64 (s, 2H), 7.53 (ddd, J=14.8, 8.4, 6.4 Hz, 2H), 7.26 (t, J=8.7 Hz, 2H), 7.12 (d, J=5.3 Hz, 1H), 4.94 (d, J=46.1 Hz, 1H), 3.05 (dd, J=32.9, 12.7 Hz, 2H), 2.66-2.34 (m, 3H), 2.07 (s, 1H), 1.53 (dt, J=23.8, 11.5 Hz, 1H). ESIMS m/z=449.1 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=O.[NH2:18]/[C:19](/[CH3:23])=[CH:20]\[C:21]#[N:22]>CC(O)=O.CCOC(C)=O>[C:21]([C:20]1[CH:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][N:7]=[C:6]3[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:3])[NH:18][C:19]=1[CH3:23])#[N:22]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(C=O)cc12
Reactant: C/C(N)=C/C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CON(C)C(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.4 %

Procedure:
A mixture of 5-formyl-N-methoxy-N-methyl-1H-indazole-3-carboxamide (400 mg, 1.72 mmol) from Synthetic Preparation 6, and 3-aminocrotononitrile (299 mg, 2.12 mmol) in HOAc (5 mL) was kept at 110° C. for 2 hr. After cooling to rt, the reaction mixture was diluted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by flash chromatography to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-methoxy-N-methyl-1H-indazole-3-carboxamide (500 mg, 80.5%) (Cpd. No. 143, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=9.65 (s, 1H), 7.85 (s, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 4.58 (s, 1H), 3.78 (s, 3H), 3.44 (s, 3H), 2.03 (s, 6H) ppm.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1.Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br>CN1C(=O)CCC1.Cl>[F:18][C:4]([F:3])([F:17])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([OH:14])=[O:13])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: BrCCOCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)C1(c2ccc(C(F)(F)F)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
A suspension of NaH (60% dispersion in mineral oil (2.3 g, 60 mmol)) in NMP (80 mL) was cooled to 0° C. under nitrogen. The reaction mixture was treated with a solution of ethyl 2-(4-(trifluoromethyl)phenyl)acetate (4.672 g, 20 mmol) in NMP (20 mL) in a dropwise fashion over 10 minutes (effervescence occurred), followed by bis(2-bromoethyl)ether (2.8 mL, 22 mmol). After 15 minutes, the reaction was warmed to 23° C. After 20 hours, the reaction was diluted with a 10% HCl solution (300 mL; slowly, a lot of effervescence was observed) and extracted with diethyl ether (2×300 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 25-50% EtOAc/hexane) affording 3.76 g of 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carboxylic acid. MS m/e=275.1 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[BrH:21].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:1]([Br:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCCO
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Yield: 51 %

Procedure:
To nonadecanol (1.0 g, 3.5 mmol) was added 1500 μL hydrobromic acid (48% wt/vol). After cooling in ice, concentrated sulfuric acid (400 μL) was added and the reaction was allowed to warm to room temperature. A condenser and drying tube were placed over the reaction and the mixture was slowly heated to 120° C. The solution was kept at reflux for five hours and then cooled. The solidified product was resuspended in a mixture of ethyl acetate (50 mL) and water (10 mL). The aqueous layer was removed and the organic layer was washed with water (2×10 mL), then 5% sodium bicarbonate (10 mL) and then one final time with water. The resulting solution was dried over magnesium sulfate and filtered. The solvent was removed to provide a crude product which was purified by silica chromatography (hexanes:ethyl acetate, 80:20, as eluant) to give the desired 1-nonadecyl bromide (624 mg, 1.79 mmol, 51%). 1H NMR (CDCl3 , 300 MHz); δ3.40 (t, J=6.9 Hz, 2H), 1.83 (m, 2H), 1.41 (br s, 2H), 1.25 (s, 32H), 0.87 (t, J=6.7 Hz). 13C NMR (CDCl3' 67.93 MHz); δ33.94 32.83, 31.90, 29.65, 29.52, 29.42, 29.33, 28.75, 28.16, 22.66, 14.07. M.S. (EI+); 346 (M+), 267 (M-Br).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[C:10]([NH:11][C:3](=[O:2])[N:4]4[C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[CH2:24]4)=[CH:9][N:8]=3)=[C:16]2[CH:17]=1)#[N:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
To a solution of the compound obtained in example 6 (110 mg, 0.22 mmol) in anhydrous DMF (3 mL), N,N-dimethylsulfamoyl chloride (0.03 mL, 0.27 mmol) and anhydrous TEA (0.13 mL, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 39.2 mg of the titled compound (38% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:19]=[CH:18][C:7]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[N+:20]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][CH2+:42]1SC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[C:45](=[O:46])[C:44](=[C:47]2[N:51]([CH3:52])[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[S:48]2)[S:43][C:42]1=[N:20][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:18]=[CH:19][C:4]=1[NH:3][CH2:1][CH3:2])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCNc1ccc(NC(=O)CN2CCOCC2)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN2CCOCC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDC3): δ 8.87 (1H, s), 7.49–7.53 (3H, m), 7.28–7.37 (5H, m), 7.19 (1H, t), 7.12 (1H, dd), 7.04 (1H, d), 6.57 (1H, d), 5.19 (2H, s), 3.79 (8H, br s), 3.16 (2H, s), 3.01 (2H, q), 2.66 (4H, br s), 1.06 (3H, t); MS(ESI): 615(MH+).