Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[O:26]=[S:2]1(=[O:1])[CH:3]=[CH:4][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of methyl (5R)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinecarboxylate (Step 2, 0.73 g, 1.87 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.27 g, 5.6 mmol) in dioxane (9 mL) is heated to 100° C. for two days. The solution is cooled and treated with 20 mL of 10% aqueous Na2SO3 and stirred for 30 minutes. The solution is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with satd NaHCO3 and saline and dried (MgSO4), filtered and concentrated. The crude residue is purified by column chromatography (0→5% ethyl ether-dichloromethane) to provide the title compound (0.28 g, 38%); 1H NMR (300 MHz, CDCl3): δ 3.31–3.35 (m, 2H), 3.89 (s, 3H), 4.00–4.15 (m, 3H), 4.25 (t, 1H), 5.11 (m, 1H), 5.45 (d, 1H), 6.54 (d, 1H), 7.29 (d, 2H).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH2:12])[N:11]=2)[N:8]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>CC(N(C)C)=O>[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:11]=2)[N:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2nc(I)ccc2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Compound 3C was synthesized according to a procedure analogous to that described in International Patent Publication No. WO 2008/06192 (Takeda Pharmaceutical Company Limited), which is incorporated by reference herein in its entirety. 6-Iodoimidazo[1,2-b]pyridazin-2-amine hydrochloride (4.45 g, 17.11 mmol) and cyclopropanecarbonyl chloride (1.35 mL, 18.82 mmol) were dissolved in DMA (85 mL) and stirred for 3 hours at ambient temperature. The reaction mixture was then poured into water (400 mL) resulting in the formation of a brown precipitate. The solid was filtered and dried under vacuum to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (4.2 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ=11.21 (s, 1 H), 8.26-8.17 (m, 1 H), 7.74 (d, J=9.3 Hz, 1 H), 7.49 (d, J=9.1 Hz, 1 H), 2.07-1.87 (m, 1 H), 0.97-0.77 (m, 4 H) ESI-MS:m/z 329.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][N:19]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:39]([Cu])#[N:40]>CN(C=O)C>[C:39]([C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][N:19]([C:31]2[N:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][N:36]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:40]
Reactant: N#C[Cu]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(CC)cn2)cc1Br
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(CC)cn2)cc1C#N

Procedure:
A solution of ethyl 2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (from step 1 in the previous example) (188 mg; 0.32 mmol) in DMF (2 ml) was treated with CuCN (37 mg; 0.41 mmol) and heated to reflux overnight under a nitrogen atmosphere. Upon cooling, the reaction mixture was filtered through a plug of silica gel and eluted with DMF. The filtrate was concentrated and partitioned between dichloromethane and brine. The organic phase was dried over MgSO4, filtered and concentrated to afford ethyl 2-[2-cyano-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (153 mg), which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[O:10][CH2:9]2)[CH2:3][CH2:2]1.[OH-].[NH4+:12]>>[NH2:12][CH2:9][CH:8]([OH:10])[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: C1CN(CC2CO2)CCO1
Agent: [OH-]
Product: NCC(O)CN1CCOCC1
Reaction time: 72 h

Procedure:
500 mg of the 1-morpholino-2,3-epoxypropane prepared as described above were dissolved in 20 ml of a saturated methanolic solution of ammonium hydroxide, and the mixture was allowed to stand at room temperature for 3 days. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, to give 530 mg of 1-amino-3-morpholino-2-propanol.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7](Cl)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[Si:14]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:23]=2)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(B(O)O)c1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Product: CC(C)(C)N1C(=O)C=C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)S1(=O)=O

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 9-A and 3-(t-butyldimethylsilyoxy)phenylboronic acid as the starting materials. 1H NMR (500 MHz, CDCl3): δ 7.37–7.36 (m, 2H), 7.25–7.24 (m, 1H), 7.03–7.01 (m, 1H), 6.61 (s, 1H), 1.73 (s, 9H), 0.99 (s, 9H), 0.23 (s, 6H); LCMS found for C19H29NO4SSi (M+H)+: m/z=418.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: CCC(Br)C(=O)O
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Product: CC[C@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: [OH:1][C@H:2]([CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])=[O:15])[CH2:3][NH:4]C(=O)OC(C)(C)C.O[C@@H](CNS(C1C=CC=CN=1)(=O)=O)CNC(=O)OC(C)(C)C.Cl.[C:46](=[O:75])(OC1C=CC([N+]([O-])=O)=CC=1)[O:47][C@H:48]([CH2:53][N:54]1[C:58]2[CH:59]=[C:60]([Cl:64])[C:61]([Cl:63])=[CH:62][C:57]=2[N:56]=[CH:55]1)[C:49]([CH3:52])([CH3:51])[CH3:50].C(N(C(C)C)CC)(C)C>O1CCOCC1.CN(C)C=O>[OH:1][C@H:2]([CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])=[O:15])[CH2:3][NH:4][C:46](=[O:75])[O:47][C@H:48]([CH2:53][N:54]1[C:58]2[CH:59]=[C:60]([Cl:64])[C:61]([Cl:63])=[CH:62][C:57]=2[N:56]=[CH:55]1)[C:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OC(=O)NC[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)NC[C@H](O)CNS(=O)(=O)c1ccccn1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a solution of 370 mg (1.12 mmol) of tert-butyl (2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & tert-butyl (2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 3.3 mL of anhydrous dioxane, 20 mL of a 4 N solution of hydrogen chloride in dioxane was added. The resulting solution was stirred for 60 min, during which time a white precipitate formed. The mixture was concentrated under reduced pressure and the resulting solid was dried under vacuum. A 54 mg (0.18mmol) sample of the residue was then added to a solution of 90 mg (0.2 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl 4-nitrophenyl carbonate in 2 mL of dimethylformamide. Addition of 0.22 mL (1.12 mmol) of diisopropylethylamine resulted in a light yellow solution, which was stirred for 1 d under nitrogen, and then concentrated. The residue was then partition between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a methanol:chloroform solution (1:9) to afford 44 mg (45%) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & (1s)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. ES-LCMS m/z 544 (M+H) retention time=3.60 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:30][CH2:29][CH:28]([O:27][C:26]5[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=5)[CH2:33][CH2:32]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=86%, [M+H]+=481 and 8%, [M+H]+=573.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9](CC1C=CC(OC)=CC=1)[C:10]([C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[N:21]=[C:20]([CH3:25])[N:19]=2)=[N:14][CH:13]=1)=[O:11].FC(F)(F)S(O)(=O)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[N:21]=[C:20]([CH3:25])[N:19]=2)=[N:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(CN(C(=O)c2cnc(Nc3cc(Cl)nc(C)n3)s2)c2c(C)cccc2Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1

Procedure:
The first step of the process involves reacting 2-chlorothiazole with 2-chloro-6-methylphenylisocyanate in the presence of n-butyl lithium in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide. The second step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide with 4-methoxybenzylchloride in the presence of sodium hydride in tetrahydrofuran to obtain 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The third step involves reacting 2-chloro-N-(2-chloro-6-methylphenyl)-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with 4-amino-6-chloro-2-methylpyrimidine in the presence of sodium hydride in tetrahydrofuran at reflux temperature to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide. The fourth step involves reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-N-(4-methoxybenzyl)-1,3-thiazole-5-carboxamide with trifluoromethanesulfonic acid and trifluoroacetic acid in dichloromethane to obtain N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide (Formula 1d).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[C:24]2=[CH:25][NH:26][C:27]([CH:28]=O)=[C:23]2[CH2:22][CH2:21][NH:20]1.N1CCCCC1>C(O)C>[O:17]=[C:12]1[C:11](=[CH:28][C:27]2[NH:26][CH:25]=[C:24]3[C:23]=2[CH2:22][CH2:21][NH:20][C:19]3=[O:18])[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(C(=O)N3CCCC3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)N3CCCC3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-(pyrrolidine-1-carbonyl)-1,3-dihydro-indol-2-one (46 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH:4]2[CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:6]2[CH2:7][CH2:8][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: C1CC(C2CC2)CN1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solution of 3-cyclopropylpyrrolidine (250 mg, 2.25 mmol) and DIEA (1.178 mL, 6.74 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (752 mg, 2.25 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 h before being cooled, concentrated, and charged (DCM) to a 40 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 745 mg (81%). 1H NMR (500 MHz, DMSO-d6) δ 5.05-5.00 (m, 1H), 3.25-3.19 (m, 2H), 3.15-3.11 (m, 1H), 2.94-2.90 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 2.06 (br. s., 1H), 1.73-1.69 (m, 2H), 1.29-1.27 (m, 6H), 0.72-0.69 (m, 1H), 0.45-0.40 (m, 2H), 0.16-0.10 (m, 2H). UPLC (M+H)=411.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccnc(F)c3)nc2c1
Yield: 73.9 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and azetidine (27.0 mg, 472 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (48.8 mg, 73.8%) as white solid. mp: >280° C., MS: m/z=421.0 (M+H+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:17]([O-])=[CH:16][C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:28])[C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(OCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Product: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1

Procedure:
A mixture of 50 g (0.15 mole) of 1-(2-benzoyloxyethyl)-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 119) and 200 ml of phosphorus oxychloride was heated for two hours on a steam bath. The mixture was then partially evaporated in vacuo. The mixture was then poured over ice and the solution was neutralized with sodium hydroxide. The product was separated by filtration, dissolved in dichloromethane, and the solution was washed with aqueous sodium bicarbonate solution and then dried. Evaporation provided a solid which was recrystallized from a 50:50 methanol:dichloromethane solution to provide white 1-(2-benzoyloxyethyl)-4-chloro-1H-imidazo[4,5-c]quinoline, m.p. 186°-190° C. Analysis: Calculated for C19H14ClN3O2 : %C, 64.9; %H, 4.0; %N, 12.0; Found: %C, 64.8; %H, 3.8; %N, 12.1.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([C:18]#[N:19])[CH2:17][C@@:11]1([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12](=[O:20])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([C:18]#[N:19])[CH2:17][C@@:11]1([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:12]([OH:20])[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#C[C@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#C[C@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.8 g, 47 mmol) was added to a stirred, ice-cooled solution of (1R*,5S* 6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 40) in methanol (300 ml). The reaction mixture was stirred for 30 minutes, quenched with saturated aqueous NaHCO3 and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-20%) to give the title compound (31 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:3][CH2:4][CH2:5][C:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:37](OC(=O)C)(=[O:39])[CH3:38].O>N1C=CC=CC=1.CCOCC>[C:10]([O:9][C:7](=[O:8])[C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]([O:1][C:37](=[O:39])[CH3:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@H](O)CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CCCCC[C@@H](CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Temperature: 60 °C

Procedure:
Di-tert.-butyl 2-[4-(S)-hydroxynonyl]-2-(6-ethoxycarbonylhexyl)malonate (39.0 g., 0.076 mole) is dissolved in pyridine (50 ml.). Acetic anhydride (8.2 g., 0.08 mole) is added dropwise during 15 minutes and the mixture is stirred and heated at 60° C. for 3 hours. The mixture is then cooled and treated with 300 ml. water. The oily product is taken up in ether, washed with 5% hydrochloric acid, two portions of water and brine, and dried over sodium sulfate. Distillation of the ether in vacuo leaves the title compound as a residual oil weighing 41 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14](B(O)O)[NH:15]2.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([F:10])[CH:19]=[CH:18][CH:17]=3)[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc2c(F)cccc2[nH]1
Reactant: Oc1ncc(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Oc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
A mixture of 5-bromo-3-iodopyridin-2-ol (5 g, 16.7 mmol), (4-fluoro-1H-indol-2-yl)boronic acid (4.48 g, 25.0 mmol), sodium carbonate (3.53 g, 33.4 mmol) and Pd(dppf)Cl2 (200 mg) in 1,4-dioxane (50 mL) was stirred at 100° C. for 16 hours under nitrogen atmosphere. The mixture was filtered through celite and concentrated, and the residue was diluted with water and EA. After extracted with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford crude 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyridin-2-ol (3.5 g) through the column chromatography (DCM:EA=5:1). Finally the pure 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyridin-2-ol (2.7 g, yield: 52%) was obtained by recrystallized from DCM:MeOH (10:1). 1H-NMR (DMSO-d6, 400 MHz) δ 12.36 (br s, 1H), 11.79 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H), 7.39 (s, 1H), 7.30 (d, J=8.00 Hz, 1H), 7.04˜7.07 (m, 1H), 6.74˜6.78 (m, 1H). MS (M+H)+: 307/309.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]>[Cl-].[Mn+2].[Cl-]>[OH:1][CH2:2][C:3]([C@@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Mn+2]
Agent: [Cl-]
Product: O=C(CO)[C@H](O)[C@H](O)[C@H](O)CO

Procedure:
The activity of the ketose 3-epimerase enzyme before purification may be measured by measuring the amount of D-psicose produced with a D-fructose substrate. Specifically, an enzyme reaction mixture composition containing 50 mM tris-HCl buffer (pH 7.0; 200 ml), 0.2 M D-fructose (375 μl), enzyme liquid (100 μl), and 10 mM manganese chloride (75 μl) is allowed to react at 55° C. for 30 min, and the reaction is quenched by boiling the mixture for 2 min. The resulting liquid composition is then measured by HPLC. One unit of enzyme activity is defined as the amount of enzyme that epimerizes D-fructose and produces 1 μmol of D-psicose per minute under the foregoing conditions. The enzyme unit for the epimerization of D-psicose to D-fructose in the reverse reaction is defined in the same manner through measurement performed under the same conditions.
Reaction SMILES: [Cl-:1].[Cl-].[C:3](=[Zr+2:6]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21]1)[CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8]1)([CH3:5])[CH3:4]>O=[Pt]=O.C(Cl)Cl>[Cl-:1].[Cl-:1].[C:3](=[Zr+2:6]([CH:20]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21]1)[CH:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8]1)([CH3:4])[CH3:5]
Reactant: CC(C)=[Zr+2](C1C=C(C(C)(C)C)c2ccccc21)C1C=C(C(C)(C)C)c2ccccc21
Agent: O=[Pt]=O
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)=[Zr+2](C1C=C(C(C)(C)C)C2=C1CCCC2)C1C=C(C(C)(C)C)C2=C1CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 167.2 %

Procedure:
In a 100 ml glass-autoclave were introduced 0.66 g of rac-isopropylidene-bis(3-t-butyl-indenyl)zirconium dichloride, 40 mg of PtO2 and 50 ml of CH2Cl2. 5 atm of H2 were pressurized in and the mixture was stirred for 4 hours at room temperature. The mixture was filtered, the filtrate brought to dryness and 0,56 g of a yellow solid was isolated, which was further purified by washing with hexane and Et2O. 0,22 g of a yellow powder were thus obtained. 1H-NMR (CDCl3): 5.3(s), 2.6-2.9(m), 2.2-2.4(m), 1.85(s), 1.4-1.8(m), 1.3(s).