Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.Cl[C:15]1[C:16](=[O:29])[NH:17][C:18]2[C:23]([N:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2>CN1C(=O)CCC1>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[C:15]1[C:16](=[O:29])[NH:17][C:18]2[C:23]([N:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2
Reactant: C[C@H]1CN(c2ccccn2)CCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of (S)-3-methyl-1-(pyridin-2-yl)piperazine (748 mg, 4.22 mmol) in NMP (5 ml), was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1 g, 4.19 mmol). After stirring 1 h at 140° C., the resulting solution was quenched by the addition of water (100 ml) and filtered to give (S)-methyl 3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (1.07 g, 67%).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20][CH:19]=[CH:18][CH:17]=2.O.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:2]([C:1]1[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:22]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cnc3cccnc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Freshly distilled trimethyl orthovalerate (41 mL, 0.24 mole) was added to a mixture of 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (39 g, 0.12 mole) in warm xylene (500 mL). The reaction mixture was heated at reflux overnight. Thin layer chromatography showed that at least half of the starting material was still present. p-Toluenesulfonic anhydride monohydrate (6 g) was added. After a short time thin layer chromatography showed that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was concentrated under vacuum to provide an oily residue. The residue was triturated with hexane to provide a dark pink solid. This solid was recrystallized from acetonitrile to provide 1,1-dimethylethyl N-[4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a pale peach solid, m.p. 96.0-98.0° C. Analysis: Calculated for C22H31N5O2: %C, 66.47; %H, 7.86; %N, 17.62; Found: %C, 66.29; %H, 7.78; %N, 17.76.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH2:13]2)=[O:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:33]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:17]2)=[O:11])=[O:8])=[CH:25][CH:26]=1)(=[S:33])[NH2:2]
Reactant: S
Reactant: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C#N)cc2)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C(N)=S)cc2)CC1

Procedure:
In a similar manner to Example 1, starting material step (b), the product from step (c) (1.2 g), pyridine (84 ml), triethylamine (7 ml) and H2S gas were reacted to give ethyl N-[N-(4-thiocarbamoylbenzoyl)carbamoyl]piperidin-4-yloxyacetate (0.74 g) as a yellow gum: NMR Spectrum (DMSO-d6) 1.20 (3H, t), 1.50 (2H, m), 1.87 (2H, m), 3.20 (2H, m), 3.66 (3H, m), 4.12 (2H, q), 4.15 (2H, s), 7.90 (4H, m), 9.63 (1H, br s), 10.00 (1H, br s); Mass Spectrum m/Z 394 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:18])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:21]1([CH2:20][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[C:7]2=[O:18])[CH2:23][CH2:22]1
Reactant: COc1ccccc1-n1cc(CC(C)C)[nH]c1=O
Reactant: BrCC1CC1
Product: COc1ccccc1-n1cc(CC(C)C)n(CC2CC2)c1=O

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-methoxy-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 42, 150 mg) by alkylation with bromomethylcyclopropane (90 mg). 3-Cyclopropylmethyl-4-isobutyl-1-(2-methoxy-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (52 mg). MS (ESI): 301.2 (MH+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@H:11]([C:12]2([CH3:17])[CH3:16])[C@@H:10]1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[S:27]([NH:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@H:11]([C:12]2([CH3:17])[CH3:16])[C@@H:10]1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)[C@H]2C[C@H](N)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H]2C[C@H](NS(C)(=O)=O)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Reaction time: 1 h

Procedure:
Triethylamine (1.9 ml) was added to a solution of (1S,2S,3S,5R)-3-amino-2-[2-(2-tetrahydropyranyloxy)ethyl]-6,6-dimethylbicyclo[3.1.1]heptane (3.25 g) in methylene chloride (30 ml). The reaction solution was cooled. To the above solution, mesyl chloride (1.0 ml) was dropped slowly. The reaction solution was allowed to stand for 1 hour. The reaction solution was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (3.05 g) having the following physical data.
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[N:9][C:10]([OH:17])=[CH:11][N:12]=2)[N:7]=1)(=O)C.[OH-].[K+].O>C(O)C>[OH:17][C:10]1[N:9]=[C:8]2[C:13]([C:14](=[O:16])[NH:15][C:6]([CH2:5][OH:4])=[N:7]2)=[N:12][CH:11]=1
Reactant: CC(=O)OCc1nc2nc(O)cnc2c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(CO)nc2nc(O)cnc12

Procedure:
A mixture of 4.0 g (0.0169 mole) of 2-acetoxymethyl-7-hydroxy-4(3H)-pteridinone, 1.2 g (0.0214 mole) of potassium hydroxide and 5 ml of water in 80 ml of ethanol is refluxed for 4 hours. After cooling, the reaction mixture is filtered. The solid thereby isolated is washed with 30 ml of ethanol and taken up in 160 ml of water. The cloudy solution obtained is clarified by filtration and acidified with acetic acid to pH 3.6. The precipitate formed is isolated by filtration. It is purified by washing with ether and recrystallization from a mixture of ethanol and N,N-dimethylformamide. Yld: 2.0 g (61%), m.p. >300° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:4].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:11][CH:10]=1)=[O:4]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccc(I)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccc([C@@H]3C[C@H]3N(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C(F)(F)F)cc2)cn1
Temperature: 85 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a 10-mL microwave tube were added tert-butyl 4-((2,2,2-trifluoro-N-(trans-2-(4-iodophenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate (300 mg, 0.543 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (136 mg, 0.652 mmol), potassium carbonate (263 mg, 1.901 mmol), acetonitrile (2 mL) and water (0.500 mL), and the mixture was degassed by bubbling N2 through. Tetrakis (31.4 mg, 0.027 mmol) was added and the tube was sealed. The mixture was stirred at 85° C. for 4 h. The mixture was cooled and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 120 mg of product as pale yellow solid. MS: (M+H)+=507.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.08-1.20 (m, 2H), 1.43-1.54 (m, 10H), 1.57-1.78 (m, 3H), 1.95-2.10 (m, 2H), 2.40-2.86 (m, 3H), 3.16 (d, J=3.54 Hz, 1H), 3.38-3.63 (m, 2H), 3.90-3.98 (m, 3H), 4.00-4.19 (m, 2H), 7.09-7.18 (m, 2H), 7.46-7.55 (m, 2H), 7.77-7.84 (m, 1H), 7.90-7.97 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](Cl)[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:20]=1[NH2:21].CC(C)([O-])C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][C:20]3[C:19]([F:18])=[CH:25][C:24]([F:26])=[CH:23][C:22]=3[F:27])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1nc2ccc(Br)cc2c2c(Cl)nccc12
Reactant: Nc1c(F)cc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cc(F)c(Nc2nc3ccc(Br)cc3c3c(Cl)nccc23)c(F)c1
Temperature: 85 °C

Procedure:
To a solution of 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine (800 mg, 2.4 mmol) in THF (10 mL) were added 2,4,6 trifluoroaniline (359 mg, 2.4 mmol) and sodium tert-butoxide (703 mg, 7.32 mmol) and the reaction mixture was heated to 85° C. for 45 min. The solution was cooled to room temperature, quenched with methanol and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% hexane to 100% EtOAc, gradient elution) to afford 9-bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine. 9-Bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine was taken up in THF (10 mL) and 6 N HCl (10 mL) and heated to 85° C. for 2 hr. The reaction was cooled to room temperature, neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layers were dried over Mg2SO4, filtered, and concentrated. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH3:17][N:18]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:19](=[O:20])[N:18]([CH3:17])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(C)C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 74.1 %

Procedure:
Into 80 ml of dichloromethane, were dissolved 10.8 g of 1-(p-fluorophenyl)piperazine and 6.1 g of triethylamine. To the solution, while being stirred and cooled in ice, was added dropwise 10.0 g of 2,4,4-trimethylallophanoyl chloride. After one hour of reaction at room temperature, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a mixture of ethanol and ether to obtain 13.7 g (74% yield) of 1-(p-fluorophenyl)-4-(2,4,4-trimethylallophanoyl)piperazine having a melting point of 83°-84° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 5.0 g of 4-amino-1-benzylpiperidine in 100 ml of dichloromethane were added 4.1 ml of pyridine and 2.2 ml of methanesulfonyl chloride at 0° C. Then the mixture was reacted at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were taken up by filtration to thereby give 7.0 g of the title compound as colorless crystals.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>CN(C(OC)OC)C>[CH3:3][N:4]([CH3:12])/[CH:5]=[CH:15]/[C:2](=[O:1])[CH2:3][N:4]1[C:5](=[O:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13]
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(2-oxopropyl)isoindoline-1,3-dione (1 g, 4.9 mmol) in 20 mL of DMF-DMA was added some of 4 A molecular sieve. The reaction mixture was stirred at 100° C. under N2 for 15 hr. After cooling down to RT, the mixture was filtered and collected 600 mg (47.5%) of crude (E)-2-(4-(dimethylamino)-2-oxobut-3-enyl) isoindoline-1,3-dione as a solid. MS (ESI) m/e [M+1]+ 259.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]#[N:27])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[K+]>C(O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]([NH2:27])=[O:30])[C:15]=2[O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C(N)=O)cnc12
Yield: 66.7 %

Procedure:
1-Benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (500 mg, 1.30 mmol) prepared in Example 276 was diluted with a mixture of ethanol (8 ml) and water (2 ml). Potassium hydroxide (650 mg, 13.0 mmol) was added to the reaction mixture, which was then refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, (v/v)) to give 350 mg of the titled compound as a white solid.
Reaction SMILES: CS(C1C=CC(C(O)=O)=CC=1)(=O)=O.O[C:15]1[C:23]2[N:22]=NN[C:19]=2C=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:32]2[CH2:35][CH:34]([NH:36]C(=O)C3C=CC(S(C)(=O)=O)=CC=3)[CH2:33]2)=[CH:27][CH:26]=1>CN(C)C=O.ClCCl>[CH:31]([N:32]=[C:33]=[N:22][CH:23]([CH3:19])[CH3:15])([CH3:49])[CH3:28].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[N:32]2[CH2:33][CH:34]([NH2:36])[CH2:35]2)=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)NC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N=C=NC(C)C
Product: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
By carrying out the operation according to the procedure of Example 31, starting with 58.5 mg of 4-methylsulfonylbenzoic acid, 26.4 mg of hydroxybenzotriazole in solution in 0.5 cm3 of dimethylformamide, 0.0302 cm3 of diisopropylcarbodiimide, a solution of 30 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 0.5 cm3 of anhydrous dichloromethane, and 3 cm3 of anhydrous dichloromethane, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methylsulfonylbenzamide is obtained in the form of a white crystals [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 3.03 (mt: 2H) 3.09 (s: 3H); 3.61 (broad t, J=7.5 Hz: 2H); 4.35 (s: 1H); 4.73 (mt: 1H); 6.55 (broad d, J=7.5 Hz: 1H); from 7.20 to 7.35 (mt: 8H); 7.96 (d, J=8 Hz: 2H); 8.03 (d, J=8 Hz: 2H)].
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCNCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
N-(3-((tert-butyl(dimethyl)silyl)oxy)propyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.540 g, 1.01 mmol) and thiophenol (0.333 g, 3.02 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.557 g, 4.03 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave the title compound as a yellow oil (0.294 g, 83% yield). No further purification was performed and the mixture was carried forward to the next step. LCMS: m/z 351 (M+H+), 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6H) 0.90 (s, 9H) 1.75 (quin, J=6.46 Hz, 2H) 2.69-2.72 (m, 2H) 2.72-2.80 (m, 4H) 3.00-3.11 (m, 8H) 3.70 (t, J=6.02 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[O:16])=[CH:10][CH:9]=1>C(Cl)Cl.C1(N=C=N)CCCCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:23]([C:20]1[S:19][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[CH:13][CH:12]=2)=[N:22][CH:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cnc(NC(=O)Cc2ccc(N)cc2)s1
Reactant: COCC(=O)O
Agent: CN(C)c1ccncc1
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCC(=O)Nc1ccc(CC(=O)Nc2ncc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methoxyacetic acid (41 μl, 0.53 mmol) in CH2Cl2 (1.5 ml), N-cyclohexylcarbodiimide, N′-methyl polystyrene (0.53 g, loading 2 mmol/g, 1.064 mmol), previously washed with CH2Cl2 (5 ml×3), 4-DMAP (0.032 g, 0.266 mmol) and a solution of 2-(4-aminophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide (0.076 g, 0.266 mmol) in CH2Cl2/DMF (0.4 ml/10.6 ml) were added. The reaction mixture was maintained under stirring at room temperature for about 72 hours the resin was filtered, washed with CH2Cl2 (10 ml×3), the filtrated combined, washed with water, 5% hydrochloric acid, water, saturated sodium bicarbonate and water, dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:24]([CH2:26][C:27](O)=[O:28])#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:27](=[O:28])[CH2:26][C:24]#[N:25])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)CC#N)CC4C3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (401.6 mg, 1.20 mmol), 2-cyanoacetic acid (110.3 mg, 1.30 mmol) in a mixture of DCM and DMF (4/1 (v/v)), 50 mL) were added HATU (555.6 mg, 1.46 mmol) and Et3N (375.6 mg, 3.71 mmol). The reaction mixture was stirred at rt overnight, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a beige solid (350 mg, 72.8%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[N:20]1([CH2:25][CH2:26][NH:27][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCCC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 97 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (2-pyrolidin-1-yl)ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (97% yield). LC/MS: RT 1.95 min; m/e 380 (M+H); 1H NMR (δ, ppm): 11.86 (1H, s), 8.44 (1H, br t), 7.53 (1H, s), 7.24 (1H, d); 6.74 (1H, d), 3.0-3.89 (8H), 2.39 (5H), 1.85 (4H), 1.09 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:5]=2[N:6]=1.[CH2:14]([I:16])[CH3:15]>>[I-:16].[CH2:14]([N:6]1[C:5]2[CH:7]=[C:8]([CH3:13])[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[S:3][CH:2]1[CH3:1])[CH3:15]
Reactant: COc1cc2sc(C)nc2cc1C
Reactant: CCI
Product: CCN1c2cc(C)c(OC)cc2SC1C
Product: [I-]
Temperature: 100 °C

Procedure:
6 g of 2,5-dimethyl-6-methoxy-benzothiazole and 60 ml of ethyl iodide were reacted in a pressure flask heated to 100° C. on an oil bath for 3 days. After cooling, the raw product was washed by grinding with ether and acetone and dried in a desicator. It was then crystallized from ethanol, thus obtaining 54 g of a crystalline product melting at 249°-252° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](Cl)=[O:33]>>[F:28][C:29]1[CH:30]=[C:31]([C:32]([N:8]2[CH2:13][CH2:12][C@H:11]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C@H:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9]2)=[O:33])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Product: CN1CCN([C@H]2CCN(C(=O)c3cc(F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=450.5 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-phenyl-piperidin-4-one, N-methyl-piperazine and 3-fluoro-5-trifluoromethyl-benzoyl chloride.