Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C([NH:7][C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[O:18][CH2:19][C:20]3[CH:21]=[N:22][S:23][C:24]=3[C:11]2=[CH:10][CH:9]=1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.C(OCC)(=O)C>[NH2:7][C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[O:18][CH2:19][C:20]3[CH:21]=[N:22][S:23][C:24]=3[C:11]2=[CH:10][CH:9]=1
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1cnsc1-2
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(N)ccc2c1OCc1cnsc1-2
Yield: 66 %

Procedure:
A suspension of methyl 7-tert-butylcarbonylamino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (Intermediate 75, 0.690 g) in methanol (30 mL) was treated with concentrated sulfuric acid (1.2 mL) and the resultant mixture was heated at 75° C. in a sealed vessel overnight. The mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was saturated with sodium chloride then extracted with ethyl acetate again. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 15-45% to give methyl 7-amino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (0.345 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[C:8]([C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:5]=2)[CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2O)n1
Product: COc1ccc(COc2ccc(Br)cc2-c2cc(Nc3ccc(Cl)cc3)nc(N)n2)cc1
Yield: 50 %

Procedure:
Following the method described in Example 165, 2-[2-amino-6-(4-chloro-phenylamino) pyrimidin-4-yl]-4-bromo-phenol and 4-methoxy-benzyl chloride provided the title compound (50% yield). 1H NMR (CD3OD) δ 3.76 (s, 3H, CH3), 5.16 (s, 2H, CH2), 6.37 (s, 1H, Ar), 6.89-6.92 (m, 2H, Ar), 7.28-7.30 (m, 3H, Ar), 7.39-7.42 (m, 2H, Ar), 7.69-7.32 (m, 4H, Ar).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[ClH:13].[ClH:13].[N:1]1([CH:6]2[CH2:11][C:10]3[C:25]4[C:24](=[CH:23][C:22]([O:21][CH2:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:27][CH:26]=4)[NH:28][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(N2CCCC2)CC1
Reactant: NNc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: c1ccc(COc2ccc3c4c([nH]c3c2)CCC(N2CCCC2)C4)cc1

Procedure:
Following a procedure similar to that described in Example 2A and using 4-(1-pyrrolidyl)-cyclohexanone (14.5 g.), 3-benzyloxyphenylhydrazine hydrochloride (21.8 g.), 160 ml. of absolute ethyl alcohol and 60 ml. of 4.5N ethanolic hydrogen chloride there was obtained 3-(1-pyrrolidinyl)-7-benzyloxy-1,2,3,4-tetrahydrocarbazole hydrochloride, 4 g. of which was hydrogenated, following a procedure similar to that described in Example 1C to give 1.3 g. of 3-(1-pyrrolidyl)-7-hydroxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 294°-295° C. (methyl alcohol-water).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]2[CH:12]([CH:13]=1)[C:11]([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=1)=[CH:10][CH2:9][CH2:8]2)([O-])=O>[Pd].CO.O1CCCC1>[C:19]([N:17]1[CH:18]=[C:14]([CH:11]2[CH:12]3[CH:7]([CH:6]=[CH:5][C:4]([NH2:1])=[CH:13]3)[CH2:8][CH2:9][CH2:10]2)[N:15]=[CH:16]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])C1=CC2C(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)=CCCC2C=C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1=CC2C(C=C1)CCCC2c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
7.7 g of the product obtained in Step 2 are stirred under a hydrogen atmosphere in the presence of 10% palladium-on-carbon in a methanol/tetrahydrofuran mixture. After filtration and concentration of the solvent, the product is used as it is in the following Step.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[N:8][OH:9])[S:2]2.[CH3:10][N:11]=[C:12]=[O:13]>C(Cl)Cl>[CH3:10][NH:11][C:12]([O:9][N:8]=[C:3]1[CH:4]2[CH2:7][CH:1]([CH2:6][CH2:5]2)[S:2]1)=[O:13]
Reactant: CN=C=O
Reactant: ON=C1SC2CCC1C2
Solvent: ClCCl
Product: CNC(=O)ON=C1SC2CCC1C2
Yield: 98.6 %

Procedure:
A solution of 6.6 g (0.046 m) of 2-thiabicyclo[2.2.1]heptan-3-one oxime, 2.9 g (0.05 m) of methyl isocyanate, and 60 ml of methylene chloride was stirred at room temperature for 17 hours. Removal of solvent gave 9.1 g of yellow-tan solid which was purified by dry column chromatography on silica gel using ether-acetone as eluent. There was obtained 5.2 g of the title product as a cream colored solid, m. 121°-2° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:44]([OH:46])=O>>[NH:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:44]([NH:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Yield: 98.6 %

Procedure:
III (8.0 g, 14 mmol) was deblocked as described for II and coupled with Boc-Gly-OH by the excess mixed anhydride method and worked up as described under III to obtain the title compound in 98.6% yield, Rf2 0.75. Anal. Calcd. for C32H43N5O8 : C 61.42, H 6.92, N 11.19%. Found: C 61.12, H 7.21, N 11.19%.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH:4]1[N:3]=[CH:1][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=CNCc1ccccn1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccn2cncc2c1
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-Formamidomethylpyridine (39 g., 0.29 mole) was dissolved in 150 ml. of benzene. Phosphorus oxychloride (100 ml.) was added dropwise at such a rate that the reaction began to reflux. By external heating, reflux was maintained for 3.5 hours. After standing approximately 16 hours at room temperature, the reaction was concentrated to an oil. The oil was poured onto approximately 300 g. of ice, the mixture made basic (approximately pH 10) with 10 N sodium hydroxide, and extracted with three 300 ml. portions of methylene chloride. The aqueous was made more basic and extracted with a further three 300 ml. portions of methylene chloride. All of the extracts were combined, back-washed with 75 ml. of water and concentrated to yield crystalline imidazo[3,4-a]pyridine (29 g., Rf 0.25 on thin layer chromatography on silica gel with ethylene acetate/5% acetic acid as eluant).
Reaction SMILES: C[N:2](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][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:29]=[C:30]([NH:34]N)[CH:31]=[CH:32][CH:33]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:36])[F:37])[CH:29]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc(OC(F)(F)F)c1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(OC(F)(F)F)c3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 43. MS: M=477.2 (M+H)+
Reaction SMILES: [C:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Pd].C(O)C>[CH:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=C(O)c1cccc(C2=CCCC2)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A mixture of 6-cyclopentenyl-pyridine-2-carboxylic acid (0.08 g, 0.42 mmol) and palladium on carbon (10% w/w, 0.04 g, 0.3 mmol) in ethanol (10 mL) was charged with a hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to obtain the crude product as white solid (0.08 g, 99%) which was used directly in the next step without further purification; MS (EI): m/e=192.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH2:7]([O:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH2:21])=[N:17][NH:16][C:15]=2[CH:14]=1)=[O:12])[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:7]([O:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH2:21])=[N:17][N:16]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[C:15]=2[CH:14]=1)=[O:12])[CH2:8][CH3:9]
Reactant: CCOC(=O)Cl
Reactant: CCCOC(=O)c1cc2[nH]nc(N)c2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of ethyl chlorocarbonate (4.90 mL, 51.7 mmol) in tetrahydrofuran (THF, 60 mL) was slowly added to a mixture of 3-Amino-1H-furo[3,2-c]pyrazole-5-carboxylic acid propyl ester (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 mL, 301 mmol) in THF (300 mL), maintaining the temperature between −5 and −10° C. The reaction was kept at the same temperature for 5 minutes then allowed to reach room temperature. The obtained mixture was evaporated to dryness under vacuum and the residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulphate and evaporated to dryness. The resulting raw material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18](C(NCCCCCCCCCCC)=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].FC(F)(F)C(O)=[O:44]>ClCCl>[NH2:1][C@H:2]([C:18]([OH:19])=[O:44])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCCCCCCCCCCNC(=O)C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O

Procedure:
The 7,2 g of 1j were dissolved in 30 ml of dichloromethane and 15 ml of trifluoroacetic acid were added. The Boc group was immediately removed. After concentration, adding of ether and washing with NaHCO3, the organic phase was dried and concentrated. The Lys(Z) [C(O)NH(CH2)10CH3 ][NH2 ] formed was allowed to reactwith C8F17CH2CH2CO2H (7,6 g, 1,34.10-2 mole); 2.7 g of DCC (1.34.10-2 mole) and 100 mg of HOBT. The peptidiccoupling was carried out in dimethylformamide (DMF). After 24 h the DCU wasfiltered and the product was crystallized.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[K].O.[CH:14](=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[O:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[CH:14]=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 170 °C
Reaction time: 1.5 h

Procedure:
The 2-(5-chloro-2-nitrophenoxy)benzaldehyde was prepared as follows: To 16.2 g of 2,4-dichloronitrobenzene stirred at 170° was added 7.1 g of the potassium salt of salicylaldehyde, monohydrate, in portions over 1.5 hours. The mixture was stirred at 170° C. for two hours, triturated with 150 ml of CH2Cl2 and filtered. The filtrate was evaporated to a red oil and the excess dichloronitrobenzene was removed by steam distillation to leave the product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: ClCCN1CCCC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CC2c1ccccc1

Procedure:
The title compound, MS: m/e=568.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:4]=1[CH:5]=[O:6].C(N(CC)CC)C.[C:19]([O:23]C)(=[O:22])[CH:20]=[CH2:21]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:21]=[CH:20][C:19]([OH:23])=[O:22])=[O:6]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(I)cc1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)O)cc1C=O
Temperature: 67.5 °C

Procedure:
2-Methoxy-5-iodobenzaldehyde (1.0 g, 3.82 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (3.71 ml, 26.7 mmol) and methyl acrylate (0.686, ml, 7.63 mmol) are added dropwise with stirring to the solution, followed by four portions of 0.0214 g of tri-o-tolylphosphine (0.095 mmol) and 0.008 g of palladium (II) acetate (0.047 mmol) at 1 hour intervals. The mixture is then heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is dissolved in dichloromethane. The resulting solution is percolated through silica gel eluting with a mixture of hexane-ethyl acetate (6:4). The percolate is evaporated to dryness, re-dissolved in 20 ml of methanol and 10 ml of 20% aqueous potassium carbonate solution added. The mixture is stirred for 6 hours at room temperature and concentrated under reduced pressure to a third of its volume. The solution is taken to a pH value of 1 with concentrated hydrochloride acid and the precipitate is filtered and recrystallized from isopropanol, to give 0.472 g of 3-formyl-4-methoxycinnamic acid (2.29 mmol) as a crystalline white solid. A second harvest obtained by concentration of the mother liquor gave an additional 0.105 g.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=3)[O:11][C:9]=2[N:10]=1.Br[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:22])[C:17]([O:21][CH2:28][C:29]([OH:31])=[O:30])=[C:18]([CH3:20])[CH:19]=3)[O:11][C:9]=2[N:10]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 430 mg of 4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol, 0.2 ml of tert-butyl bromoacetate and 423 of mg potassium carbonate in 5 ml of dimethylformamide was stirred at 60° C. for 2 h. After cooling, the solids were removed by filtration and the solvent were distilled off in vacuo. 1.3 ml of trifluoroacetic acid were added to the residue, and the solution was stirred at room temperature for 1 h. Then 10 ml of toluene were added and the solvents were removed in vacuo. The title compound was isolated by silica gel chromatography (heptane/ethyl acetate gradient) as a white solid (135 mg).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12](=O)[CH3:13])=[CH:7][C:6]=1[F:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([CH:12]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:13])=[CH:7][C:6]=1[F:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(F)c(OCC(F)F)c(F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cc(F)c(OCC(F)F)c(F)c1
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (750 mg, a white solid) from 1-(4-(2,2-difluoroethoxy)-3,5-difluorophenyl)ethanone (590 mg, 2.5 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCl>[CH3:1][S:2]([NH:5][C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)=[O:20])(=[O:4])=[O:3]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of methylsulphonamide (5.37 g, 57 mmol) in anhydrous dichloromethane (100 ml), cooled to 0° C. was treated with triethylamine (7.9 ml, 57 mmol) followed by a solution of 3-nitrobenzoyl chloride (10 g, 54 mmol) in anhydrous dichloromethane (100 ml) dropwise. After stirring for 2 h at 0° C., the reaction mixture was washed with 1M HCl (100 ml). The precipitate which formed was collected by filtration and triturated with diethyl ether and was then recrystallised from hot methanol to afford the title compound (4.3 g, 31%) as a colourless crystalline solid, mp 175°-178° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.42 (3H, s), 7.82 (1H, dd, J=8.0 and 8.0 Hz), 8.38 (1H, d, J=8.0 Hz), 8.49 (1H, d, J=8.0 Hz), 8.80 (1H, s).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:29][NH2:30])=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:29][NH:30][C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36](=[O:37])[O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
DIPEA (1.1 g, 8.3 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.0 g, 2.48 mmol) in DMF (10 mL). 3-((tert-Butoxycarbonyl)amino)propanoic acid (0.39 g, 2.07 mmol) and HATU (0.90 g, 2.48 mmol) were then added. The reaction mixture was stirred at 0° C. for 1 h and then was quenched with saturated sodium chloride (50 mL). The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 2:1 hexanes/EtOAc) to afford tert-butyl (3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl)carbamate (1.0 g, 87%). ESI-MS (EI+, m/z): 462 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].S(F)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:28])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: COS(=O)(=O)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 30 ml of dry dimethlformamide was dimethylformamide 0.6 g of about 50 % sodium hydride, and stirring was performed for 30 minutes. To this was added dropwise 2.3 g of methyl fluorosulfate and the mixture was reacted for one hour at room temperature. Then the mixture was neutralized with 5 % sodium carbonate solution and concentrated under reduced pressure to leave a residue, to which was added water to yield a crude product. This products was recrystallized from acetone to give 2.6 g of 1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 234°-235°C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:20][CH3:21])[C:10]([S:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1.[NH3:23]>CO>[CH3:22][C:4]1[CH:3]=[C:2]([NH2:23])[N:7]2[N:8]=[C:9]([S:20][CH3:21])[C:10]([S:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1cccnc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1cccnc1

Procedure:
In an analogous manner to that described in Example 4), from 7-chloro-5-methyl-2-methylsulphanyl-3-(pyridine-3-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(pyridine-3-sulphonyl) -pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 226.8 -227.5°.