Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[CH:45]=[CH:44][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21](C(OC(C)(C)C)=O)[N:22]=2)=[O:16])=[CH:13][CH:12]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[C:19]4[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[O:34])[S:30][C:20]=4[NH:21][N:22]=3)=[O:16])=[CH:44][CH:45]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN1CCCN(Cc2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide, followed by 138 μL (1.11 mmol) of N-methyl-homopiperazine, are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then treated with ice. It is then extracted with ethyl acetate and twice with dichloromethane. The organic extracts are combined and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 3 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (1 injection: conditions B′; 3 injections: conditions B). 53 mg of 4-(4-methylperhydro-1,4-diazepin-1-ylmethyl)-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder. LC-MS-DAD-ELSD: 516(−)=(M−H)(−); 518(+)=(M+H)(+).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.[OH-].[Na+].[CH3:16][N:17]=[C:18]=[S:19].Cl>O1CCCC1>[NH2:1][C:2]1[N:3]([C:18]([NH:17][CH3:16])=[S:19])[N:4]=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=1
Reactant: CN=C=S
Reactant: Nc1n[nH]c(Cc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=S)n1nc(Cc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
The synthesis method of Example 7-(3) was applied. The compound (6.17 g) obtained in (1) above, a 0.77N aqueous sodium hydroxide solution (40 ml), methyl isothiocyanate (2.86 g) and tetrahydrofuran (40 ml) were used as reagents and the mixture was stirred at room temperature for 17 hours. 2N Hydrochloric acid (19 ml) was added to neutralize the mixture. The resulting crystals were collected by filtration and washed with hexane-ethyl acetate to give 3.55 g of white powdery crystals (yield 40%).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16](N)=O.O>O1CCCC1.ClCCl>[C:2]1([C:1]2[N:8]=[C:16]([C:15]3[CH:14]=[CH:22][N:21]=[CH:20][CH:19]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: Cc1cnccc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2noc(-c3ccncc3)n2)cc1
Temperature: 50 °C
Yield: 25.2 %

Procedure:
To a mixture of benzamide oxime (12.8 g, 94 mmol) and 4 Å sieves (80 g) in tetrahydrofuran (250 ml) under a nitrogen atmosphere was carefully added sodium hydride (55% dispersed in oil, 4.3 g, 98 mmol) portionwise. When addition was complete the reaction was heated at 50° C. for 1 hour. Methyl isonicotinamide (5.6 ml, 47 mmol) in tetrahydrofuran (50 ml) was added, and the reaction stirred at reflux for 2 hours. The reaction was cooled to room temperature and water (200 ml) and dichloromethane (300 ml) added. The mixture was filtered through a pad of Celite and the two phases separated. The aqueous phase was extracted with a further portion of dichloromethane (250 ml). The combined organic phases were washed with saturated brine (200 ml), dried (MgSO4) and evaporated in vacuo. The residue was triturated with ethyl acetate to yield the title compound as a white solid (2.64 g, 25%). δH (CDCl3) 7.50-7.56 (3H, m, ArH), 8.05-8.07 (2H, m, ArH), 8.16-8.19 (2H, m, ArH), 8.89 (2H, dd, J 4.4, 1.6 Hz, pyridyl 2-H, 6-H).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:19][C:20]([C:22]1[NH:23][N:24]=[C:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)=[O:21])[CH3:18].[CH3:35][C:36]1([CH3:50])[O:40][CH2:39][C@@H:38]([CH2:41]O)[N:37]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:46]([O:45][C:43]([N:37]1[C@H:38]([CH2:41][N:23]2[C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])=[CH:26][C:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:24]2)[CH2:39][O:40][C:36]1([CH3:35])[CH3:50])=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Di-tert-butyl azodicarboxylate (0.56 g, 2.43 mmol) was added portionwise to a mixture of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 2.0 mmol), (R)-1-boc-2,2-dimethyl-4-hydroxymethyl-oxazolidine (0.49 g, 2.1 mmol) and triphenylphosphine (0.64 g, 2.4 mmol) in THF (10 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica; DCM in heptane 50/50 to 100/0). Desired fractions were collected and the solvent evaporated in vacuo to yield (R)-4-(5-ethoxycarbonyl-3-phenoxymethyl-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.91 g, 98% yield) as a clear oil.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15]C1C=CC(C(=O)C)=CC=1>CCOC(C)=O>[CH3:14][O:15][C:4]1[CH:3]=[CH:2][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CC(C)=O)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 3.0 g of 4′-methoxyacetophenone and 3.95 mL of EtOAc. Purification by recrystallization from toluene/hexane afforded the title compound: 1H NMR (400 MHz, CDCl3, enol form) δ7.70 (d, 2H, J=8.20), 7.34 (d, 2H, J=8.20), 6.17 (s, 1H), 3.87 (s, 3H), 2.17 (s, 3H); low resolution MS (ES)m/e 193.1 (MH+)
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([C:14](=[O:28])[C@@H:15]([NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:16]([CH3:18])[CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[Li+].[OH-]>CO>[C:20]([NH:19][C@@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([N:6]([CH2:5][C:4]([OH:29])=[O:3])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:28])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Yield: 92.5 %

Procedure:
To a solution of compound 703 (3.45 g, 8.8 mmol) in MeOH (9 mL) was added 1N LiOH (9 mL) and the reaction allowed to stir over night. The reaction was concentrated in vacuo and the residue taken up into EtOAc and H2 O. The layers were separated and the aqueous phase was acidified with 1N HCl. The product was extracted with EtOAc (2×). The extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 3.0 g of compound 704. ##STR83##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[C:3]=12.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]O)[CH2:28][CH2:27]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[C:3]=12
Reactant: CN1CCN(CCO)CC1
Reactant: Fc1ccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN1CCN(CCn2nc(-c3ccc(F)c(F)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
A mixture of 4-chloro-3-(3,4-difluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-(4-methylpiperazin-1-yl)ethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 10.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@@H:5]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:6][N:7]([C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]([NH2:28])[N:19]=2)=[CH:12][CH:11]=1)[NH2:8])C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].O.CC#N>O1CCOCC1.Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[NH2:28][C:20]1[N:19]=[C:18]([C:17]#[C:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([N:7]([NH2:8])[CH2:6][C@H:5]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:4]([OH:39])=[O:3])=[O:29])=[CH:11][CH:12]=2)[C:27]2[C:22]([CH:21]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CCOC(=O)[C@H](CN(N)C(=O)c1ccc(C#Cc2nc(N)cc3ccccc23)cc1)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: Nc1cc2ccccc2c(C#Cc2ccc(C(=O)N(N)C[C@@H](C(=O)O)S(=O)(=O)c3ccccc3)cc2)n1

Procedure:
A solution of ester 35-4 (0.46 g, 0.85 mmol) in dioxane (4 mL) and 6N HCl (8.5 mL) was heated to 60° C. overnight. Concentration yielded an orange solid. Prep. HPLC (C18, 0.1% TFA H2O/CH3CN) followed by lyophilization gave trifiuoroacetate 35-5 as an orange solid.
Reaction SMILES: ClC1C=CC=CC=1Cl.[Cl:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:11]=1[NH:12][S:32]([C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=1[Cl:21])(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 400 ml flask, 200 ml of o-dichlorobenzene, 1 ml of pyridine and 2.0 g (0.01 mole) of 2-chloro-4-trifluoromethylaniline were charged. While stirring the contents, 2.8 g (0.01 mole) of 2-chloro-5-trifluoromethylbenzenesulfonylchloride was added dropwise at room temperature over 5 minutes. Thereafter, the reaction mixture was heated and stirred for 8 hours under reflux (175°-180° C.). After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with anhydrous sodium sulfate, o-dichlorobenzene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 2. m.p. 122°-123° C., yield 2.2 g (50%).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19])[CH3:24]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 12.5 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide (U.S. Pat. No. 4,112,095) in 500 ml of dimethylformamide under argon, was added 2.47 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 4.1 ml of ethyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a Waters Prep 500 silica gel column, eluting with dichloromethane:methanol (97:3). Fractions 8-13 were combined, evaporated in vacuo and the solid recrystallized from dichloromethane-hexane, giving 6.54 g of the desired product, mp 180°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[CH2:32])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:31]([CH:28]1[CH2:27][CH2:26][CH:25]([CH:22]2[CH2:21][CH2:20][CH:19]([C:3]3[CH:4]=[CH:5][C:6]([CH:8]4[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]4)=[CH:7][C:2]=3[F:1])[CH2:24][CH2:23]2)[CH2:30][CH2:29]1)[CH3:32]
Reactant: C=CC1CCC(C2CCC(c3ccc(C4CCC(CCCCC)CC4)cc3F)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(CC)CC4)CC3)c(F)c2)CC1

Procedure:
4-[2-Fluoro-4-(4-pentylcylohexyl)-phenyl]-4′-vinyl-bicyclohexyl (No. 5) (1.5 g) obtained in Example 1 was dissolved in a mixed solvent of toluene (15 ml) and Solmix (15 ml), and Pd/C (0.20 g) was added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue was purified with a fractional operation by means of column chromatography using heptane as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 0.78 g of 4-ethyl-4′-(2-fluoro-4-(4-pentylcyclohexyl) phenyl) bi (cyclohexane) (E). The yield based on the compound (No. 5) was 51.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:5]([N:21](S(C)(=O)=O)[S:22]([CH3:25])(=[O:24])=[O:23])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=2)[C:5]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[N:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:15]1)=[O:9]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N(S(C)(=O)=O)S(C)(=O)=O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NS(C)(=O)=O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 96 h
Yield: 67.6 %

Procedure:
To a solution of 0.13 g (0.2 mmol) of N-{5-methyl-6-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-3-[3-(trifluoromethyl)phenyl]pyridin-2-yl}-N-(methylsulfonyl)methanesulfonamide (intermediate 4) in 2.0 ml of THF was added 0.2 ml (0.2 mmol) of a tetrabutylammonium fluoride solution (1M in THF) and the reaction mixture was subsequently heated up to reflux. After 4 days, the solvent was evaporated and the crude product purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.069 g (64%) of the title compound as yellow amorphous solid. MS: 511.3 (MH+).
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CCCCCC.O1CCCC1>[CH3:12][S:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(S(=O)(=O)N2CCCC2=O)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
16.95 cm3 of a 1.6M solution of n-butyllithium in n-hexane is added drop by drop to 2.29 g of 2-pyrrolidinone in solution in 160 cm3 of anhydrous tetrahydrofuran cooled to -30° C., maintaining the temperature at -30° C. After agitation for 30 minutes, the mixture is poured drop by drop into a solution containing 6 g of 4-methylthio-benzenesulphonyl chloride [J. Chem. Soc. (1948) 604] in 10 cm3 of tetrahydrofuran, operating between -30° and -25° C. The whole is left to return to ambient temperature. The solvent is evaporated off under reduced pressure, the residue is taken up in water and the solid is filtered off. After crystallization from isopropanol, 3.80 g of expected product is obtained.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH:41]([N:43](C(OC(C)(C)C)=O)/[C:44](=[N:57]/C(OC(C)(C)C)=O)/[NH:45][CH2:46][CH2:47][CH2:48][NH:49]C(=O)OC(C)(C)C)[CH3:42])[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:44](=[NH:57])[NH:43][CH:41]([C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:72]3[N:73]=[C:74]([NH2:77])[S:75][CH:76]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[CH3:42]
Reactant: CC(c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)N(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)NCCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=N)NCCCN)c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 0 °C
Yield: 39.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((E)-3-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)imino)-12,12-dimethyl-10-oxo-11-oxa-3,5,9-triazatridecan-2-yl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (0.133 mmol), TFA (410 μl, 5.32 mmol) anisole (29 μL, 0.27 mmol) and DCM (1.33 mL). The reaction mixture was cooled to 0° C. and diluted with DCM and ice water, Whereupon the layers were separated. The aqueous layer was purified by reverse phase preparative HPLC (XSELECT, C18 5 um 30×100 mm; ACN-water with 0.1% formic acid), affording the title compound (34 mg, 39%) as a white powder. LCMS: Rt=0.52 min, m/z=643.2 (M+1) Method 2m_acidic_polar. 1H NMR (400 MHz, D2O, reported as a 1:1 mixture of diastereomers) δ 7.79 (s, 1H) 7.77 (s, 1H), 7.12 (s, 1H), 7.12 (s, 1H), 5.64 (d, J=5.6 Hz, 1H), 5.61 (d, J=5.6 Hz, 1H), 5.05-4.73 (m, 8H assumed; partially obscured by solvent residual peak), 3.39-3.32 (m, 4H), 3.13-3.05 (m, 4H), 2.00 (p, J=7.0 Hz, 4H), 1.64 (d, J=3.6 Hz, 3H), 1.63 (d, J=3.7 Hz, 3H), 1.37-1.28 (m, 4H), 1.21-1.12 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH:25]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>C(O)(=O)C>[CH3:25][O:21][C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To 2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (150 mg, 0.486 mmol) in an oven dried round-bottom flask is added methanol (1.0 mL) and benzene (3.7 mL) under nitrogen, and the reaction stirred for 10 min. Trimethylsilyldiazomethane (0.34 ml, 0.678 mmol) is added and the reaction stirred for 1 h. Glacial acetic acid (0.05 ml) is then added until the yellow color has disappeared. The reaction mixture is concentrated under reduced pressure and co-evaporated with benzene. It is dried under high vacuum to yield the title compound as a white solid (155 mg, 99% yield).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]2[C:32](=[O:33])[N:31]([CH3:34])[C:24]3[N:25]=[C:26]([S:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)[CH:15]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C1COCC1>[CH3:34][N:31]1[C:24]2[N:25]=[C:26]([S:29][CH3:30])[N:27]=[CH:28][C:23]=2[CH:22]=[C:21]([C:16]2[CH:15]=[C:14]([C:13]3[O:5][N:4]=[C:2]([CH3:3])[CH:1]=3)[CH:19]=[CH:18][C:17]=2[CH3:20])[C:32]1=[O:33]
Reactant: CC(C)=NO
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ncc2cc(-c3cc(-c4cc(C)no4)ccc3C)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
Propane-2-one oxime (62 mg, 0.844 mmol) was dissolved in 2 mL THF and cooled to 0° C. under nitrogen. n-Butyl lithium (0.68 mL of 2.5 M solution in hexanes, 1.688 mmol) was added slowly, so that the reaction temperature remained below 5° C. After stirring for 30 minutes, 4-methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester (200 mg, 0.56 mmol) was added, and the reaction mixture was stirred at 0° C. for one hour. Concentrated sulfuric acid (0.43 mL) was added dropwise, and the temperature was allowed to warm to room temperature over one hour. The reaction mixture was made pH neutral by addition of 1 M aqueous NaOH, and then partitioned between water and methylene chloride. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative scale TLC plate, eluting with 25% EtOAc in hexanes then again with 0.25% MeOH in CH2Cl2, to give 8 mg of 8-methyl-6-[2-methyl-5-(3-methyl-isoxazol-5-yl)-phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one; MS (M+H)=379.