Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=O)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].N1CCCCC1>C(O)C>[C:1]1([NH:7][C:8](=[O:17])[NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[C:24]3[S:18][C:19](=[S:20])[NH:21][C:22]3=[O:23])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(Nc1ccccc1)Nc1nc(C=C2SC(=S)NC2=O)cs1

Procedure:
Following a procedure similar to that described in Example 24, the desired compound was prepared from 1 g of 2-(3-phenylureido)thiazole-4-carbaldehyde, 0.6 g of rhodanine, 0.75 g of piperidine and 15 ml of ethanol. The resulting product was a yellow-brown powder having the following physical properties.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12](Cl)[N:11]=[C:10]([S:18][CH2:19][CH2:20][CH3:21])[N:9]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:7][C:8]1[N:9]=[C:10]([S:18][CH2:19][CH2:20][CH3:21])[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N2CCOCC2)n1

Procedure:
Morpholine (2.6 g) was added dropwise to a stirred solution of 4,6-dichloro-5-nitro-2-propylthiopyrimidine (8 g) and N,N-diisopropylethylamine (3.85 g) in acetonitrile (70 ml ) at 0° C. After 1 h the solvent was evaporated and the residue partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 25% ethyl acetate in isohexane. Yield 7.1 g
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][C:6]2=[O:13])[CH3:2].C(=O)(O)[O-].[Na+].O.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:8][CH2:7][C:6]2=[O:13])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCc1ccc2c(c1)C(=O)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc2c(c1)C(=O)CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one (1.25 g) in THF (15 mL) was added sodium bicarbonate (0.84 g). Water (5 mL) followed by benzyl chloroformate (1.58 g) were added to the mixture,and it was stirred at room temperature overnight. The reaction was not complete as determined by TLC, so an additional 0.60 g of NaHCO3 were added to the mixture and it was stirred at room temperature for two additional hours. The mixture was then concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated. Chromotography on silicia gel using 25% ethyl acetate in heptane solvent solution gave 1.84 g of the title compound. MS (ESI+) for C19H19NO3 m/z 310.03 (M+H)+.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7].[NH3:19]>CO>[C:3]([CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])(=[O:18])[NH2:19]
Reactant: COC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N
Solvent: CO
Product: NC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
[(5-Chloro-1H-indole-2-carbonyl)-amino]-acetic acid methyl ester (100 mg, 0.40 mmol) was added to a saturated solution of ammonia in methanol (ca. 3 mL) at 25° C. The suspension was sonicated for 1 hour and the resulting solution concentrated. The residue was triturated with ether/hexanes and dried. Yield 77 mg, 77%; HPLC (60/40) 2.78 minutes (98%); PBMS 252/254 (MH+, 100%);
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].CCN(CC)CC.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of crude 1-(bromomethyl)-2-chloro-4-nitro-benzene (29.1 mmol; 50% pure) in 30 mL of DCM was added Et3N (4.2 mL, 30 mmol) and 1-methylpiperazine (3.4 mL, 30 mmol). After stirring for 3 h at ambient temperature, aq. NaHCO3 was added and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide 6.80 g of product as a dark yellow oil.
Reaction SMILES: [CH2:1]([C:8]([NH:38]C(=O)OC(C)(C)C)([CH2:36][OH:37])[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]([NH:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH3:28])=[O:25])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)(Cl)Cl>[NH2:38][C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:36][OH:37])[CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=1)[C:24]([NH:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH3:28])=[O:25].[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: C[C@@H](NC(=O)c1cc(CNCC(CO)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1cc(CNCC(N)(CO)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
Treatment of Boc derivative from step B with 50% TFA in CHCl3 for 30 min, followed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) afforded 3-{[(2-amino-2-benzyl-3-hydroxypropyl)amino]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a bis TFA salt. 1H NMR (400 MHz, d4-MeOH) δ 8.85 (d, J=7.9 Hz, 1H), 7.84 (s, 2H), 7.67 (s, 1H), 7.46-7.38 (m, 2H), 7.36-7.25 (m, 3H), 7.25-7.18 (m, 2H), 7.10-7.00 (m, 2H), 5.40-5.18 (m, 1H), 4.12-4.00 (m, 2H), 3.66 (A of AB, d, J=11.0 Hz, 1H), 3.61 (B of AB, d, J=11.0 Hz, 1H), 3.35 (s, 3H), 3.06-2.88 (m, 2H), 2.95 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:28]1[C:37]2[C:32](=[C:33]([NH:38][NH2:39])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1>>[CH:28]1[C:37]2[C:32](=[C:33]([N:38]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:25])([F:24])[F:26])(=[O:22])=[O:21])=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:39]3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1
Reactant: NNc1cccc2cnccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and isoquinolin-5-yl-hydrazine according to the method described for example 43. MS: M=498.0 (M+H)+
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: Nc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with aniline (0.11 g, 1.2 mmol). Purification on silica gel, eluting with 2:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/2-propanol to give 121 as a white solid (m.p. 241-242° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C1C=CC=CC=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:36]O>>[CH2:7]([C:8]1[N:9]=[N:10][C:11]2[C:6]([C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:36][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[C:26]=3[Cl:25])[CH:19]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: OCc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(COc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and (2-chloro-3-trifluoromethyl-phenyl)-methanol according the procedure of Example 55. MS (ES) m/z 538.7.
Reaction SMILES: C1C(=O)N(O[C:9]([CH2:11][CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:14]2=[O:15])=[O:10])C(=O)C1.[NH2:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>CN(C)C=O.C(Cl)Cl>[C:14]1(=[O:15])[N:13]([CH2:12][CH2:11][C:9]([NH:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:10])[C:18](=[O:19])[CH:17]=[CH:16]1
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCO[Si](CCCNC(=O)CCN1C(=O)C=CC1=O)(OCC)OCC
Reaction time: 22 h
Yield: 118.8 %

Procedure:
3-Maleimidopropionic acid N-hydroxysuccinimide ester (18) (4.0 g, 15.03 mmol, 1.0 equiv.) was dissolved in N,N-dimethylformamide (75 mL) and 3-aminopropyltriethoxysilane (17) (5.06 mL, 15.03 mmol, 1 equiv.) was added and the reaction mixture was allowed to stir for 22 hours. An aliquot (0.15 mL) was removed by syringe, concentrated in vacuo, and the resulting oil was analyzed by 1H NMR spectroscopy. The oil was consistent with desired product. The reaction mixture was then concentrated in vacuo at 50-55° C. and the residue obtained was dissolved in CH2Cl2 (75 mL), washed with water (3×50 mL) and brine (50 mL), filtered through granular Na2SO4, and concentrated under reduced pressure in vacuo to provide 6.65 g (>100% due to residual N,N-dimethylformamide) of the crude maleimide-silane (19) as a light yellow oil. Crude (19) was used without purification. 1H NMR (300 MHz, CDCl3) δ 6.65 (s, 2H), 6.00 (s, 1H), 3.77 (q, J=7 Hz, 6H), 3.70 (m, 2H), 3.17 (m, 2H), 2.46 (m, 2H), 1.56 (m, 2H), 1.18 (t, J=7 Hz, 9H), 0.57 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.36, 169.28, 134.09, 58.35, 41.77, 34.56, 34.21, 23.20, 18.20, 7.65. FB-MS (pos): [M+H]+ 373 (373.2 calcd).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:15])(=[O:14])[NH:6][C:5]=1[C:16]([O:18][CH3:19])=[O:17].S(OC)(O[CH3:24])(=O)=O>CN(C=O)C.O>[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7](=[O:14])(=[O:15])[N:6]([CH3:24])[C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 30 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a suspension of 3.5 grams (.086 moles) of sodium hydroxide in 68 ml DMF, a solution of 20 grams (.078 moles) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide is added in 34 ml DMF over a period of about 5 minutes at about 25° C. 11.9 Grams (.094 moles) of dimethyl sulphate is added over a period of about 30 minutes at a maximum temperature of 30° C. The reaction is stirred for 3 hours at 30° C. and diluted with about 150 ml of water. It is cooled to 15° C., filtered and washed well with water. After drying, there is obtained 20 grams (95%) of product, m.p. 163°-165° C.
Reaction SMILES: CC(O)CNCC(O)C.C(OC(OCC)[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)C.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][C:45](=[C:48]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH2:52][CH2:51][N:50]4[C:59]([CH:62]=[O:63])=[CH:60][N:61]=[C:49]34)[CH2:44][CH2:43]2)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(O)(=O)C>[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:62]([C:59]1[N:50]2[C:49]([C:48](=[C:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:23]5[CH:24]=[CH:25][C:26]6[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=6)[N:22]=5)=[CH:35][CH:36]=4)[CH2:47][CH2:46]3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[CH2:52][CH2:51]2)=[N:61][CH:60]=1)[OH:63]
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reactant: CCOC(OCC)n1ccnc1
Agent: CC(O)CNCC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC(c1ncc[nH]1)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: -78 °C
Yield: 98.1 %

Procedure:
A mixture of diisopropanolamine (1.13 g) in THF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:1][CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][C:8](=[O:23])[C:9]2[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC1CCCC1

Procedure:
The title compound, off-white solid, MS: m/e=417.3 [(M+H)+], was prepared in accordance with the general method of example 11 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and cyclopentanone.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH2:12])=[O:11].[NH:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:17]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=1>CN(C=O)C>[NH:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:17]([C:26]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH2:12])=[O:11])=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 16 h

Procedure:
Triethylamine (163.8 ml, 1.17 mmol) was added to a solution of H-ProNH2*HCl (118.5 mg, 0.782 mmol) in dry DMF (10 ml). Boc-p-Iodo-Phe-OSu (0.42 g, 0.86 mmol) was added in one portion and the mixture stirred for 16 h under an argon atmosphere. The solvent was evaporated and the residue treated in a standard way, i.e. the residue was partitioned between ethylacetate (60 ml) and 0.3N KHSO4 solution (10 ml). The organic layer was further washed with saturated NaCHO3 solution (10 ml), water (10 ml)and brine (5 ml). The solution was dried and evaporated at reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:40]([C:37]1[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-(trifluoromethyl)benzene sulfonyl chloride (13 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 29 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethyl)benzenesulfonamide (percentage yield: 97%), was obtained.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CO.O.[Pd]>[NH:12]1[C@H:13]([C:15]([OH:17])=[O:16])[CH2:14][C@@H:11]1[C:9]([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1C[C@H](C(=O)O)N1

Procedure:
208 mg (0.5 mmol) of stereochemically pure transor cis-N-benzylazetidine-2,4-dicarboxylic acid dibenzyl ester and 20 mg of 10% Pd/C in 15 ml of methanol are hydrogenated as above. The reaction mixture is diluted with 50 ml of warm water, filtered, and evaporated to dryness to afford as off-white solids the trans- or cis azetidine-2,4-dicarboxylic acid in virtually quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.I.[CH3:16][S:17][C:18](=[NH:24])[NH:19][N:20]=[C:21]([CH3:23])[CH3:22]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:24][CH:18]([S:17][CH3:16])[N:19]([N:20]=[C:21]([CH3:23])[CH3:22])[C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CSC(=N)NN=C(C)C
Reactant: O=C(Cl)N(C(=O)Cl)c1ccc(Cl)cc1
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(c2ccc(Cl)cc2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-(4-chlorophenyl)-bis(chlorocarbonyl)-amine and acetone-S-methyl-isothiosemicarbazone hydroiodide with addition of triethylamine, yielded 1-(4-chlorophenyl)-3-isopropylideneamino-4-methylmercaptotetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 142°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([NH2:21])=[O:20].B(F)(F)F>>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([CH:18]([C:17]([NH2:23])=[O:22])[C:19]([NH2:21])=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)CC(N)=O
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1Cl
Agent: FB(F)F
Product: NC(=O)C(C(N)=O)C(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
Another method of preparation is accomplished by the reaction of 2,4-dichlorobenzhydrol with malonamide in the presence of acid and BF3 to yield 2,4-dichlorobenzhydrylmalonamide which in turn is allowed to react with formamide in the presence of dimethyl sulfoxide and base to yield 4,6-dihydroxy-5-(2,4-dichlorobenzhydryl)pyrimidine. This dihydroxy compound is allowed to react with excess phosphorus oxychloride to yield the 4,6-dichloro-5-(2,4-dichlorobenzhydryl)pyrimidine.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>>[CH3:26][C:27]1[N:28]=[C:29]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:30][CH:31]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCOCC4)n3)c2n1
Reactant: Cc1cscn1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCOCC3)n2)n1

Procedure:
This is prepared from 7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine and 4-methylthiazole by the method of Example 38.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]CC)=O)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][NH2:27]>C(O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:26][NH2:27])=[O:23])[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{23} (5.68 g, 17.4 mmol, 1 equiv.), anhydrous hydrazine (1.6 mL, 52.2 mmol, 3 equiv.), ethanol (35.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{23} (3.60 g, 64%) as a light yellow solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.41 (dd, 4H, J=1.5, 8.5 Hz), 7.28-7.25 (m, 4H), 7.20-7.16 (m, 2H), 4.23 (s, 1H), 3.82 (br s, 2H), 3.08 (s, 2H), 2.54 (br s, 4H), 2.40 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 142.2, 128.5, 127.8, 127.0, 76.0, 60.5, 53.9, 51.8.