Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(OC(=O)C)(=O)C>>[CH2:10]1[C:11](=[O:13])[O:16][C:14](=[O:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCCCCCCCC(=O)O1
Yield: 94.2 %

Procedure:
A stirred mixture of 23 gms (0.1 mole) of 1,10-decanedicarboxylic acid and 18 gms (0.1 mole) of acetic anhydride was refluxed for 18 hours and then concentrated in vacuo to remove acetic acid and excess acetic anhydride. The residue was dissolved in 300 ml methylene chloride, filtered, washed with ice-cold 5% sodium bicarbonate solution, water, and saturated sodium chloride. After the final separation of the layers the organic solution was dried over MgSO4, filtered, and evaporated in vacuo to give 20 gms crude product. This was purified by dissolving it in 100 ml boiling methylene chloride, filtering hot, diluting with 200 ml hexanes, and refrigerating. This resulted 13 gms pure title product m.p. 85°-9°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)([O-])=O.NC1C=CC=C[C:21]=1[C:26]1[O:27]C2C=CC=CC=2N=1>C(Cl)Cl.C(O)C.O=[Pt]=O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:26](=[O:27])[CH3:21]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2ccccc2o1
Reactant: Nc1ccccc1-c1nc2ccccc2o1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound was prepared in a multistep synthesis employing Scheme 3, as described: A suspension of 2-aminophenol (5.0 g, 45.81 mmol) and 2-nitrobenzaldehyde (6.92 g, 45.81 mmol) in cyclohexane (200 mL) was heated to reflux using a Dean-Stark apparatus to remove water for 5 h. The reaction mixture was concentrated in vacuo to yield bright yellow crystals of the corresponding imine (10.71 g, 97% yield). To a solution of this imine (7.88 g, 32.56 mmol) in CH2Cl2 (200 mL) was added Ag2O (9.05 g, 39.07 mmol) and the reaction mixture was allowed to stir at RT overnight. The solvent was removed in vacuo to yield a solid shown to be the 2-(2-nitrophenyl) benzoxazole. This product was then suspended in ethanol (200 mL) with PtO2 (0.3 g) and charged with H2 (60 psi). The reaction mixture was allowed to shake on a Parr apparatus for 3 h. This was filtered through celite and the filtrate was removed in vacuo to yield a yellow solid. 1H NMR showed this to be the desired 2-(2-aminophenyl) benzoxazole, 3.85 g. This was acetylated according to General Procedure A and purified by recrystallization from cyclohexane/ethyl acetate, m.p. 125°-128° C.; 1H NMR (300 MHz, DMSO-d6) δ11.48 (s, 1H), 8.54 (d, J=9 Hz, 1H), 8.13 (dd, J=1.5, 9 Hz, 1H), 7.80-7.75 (m, 2H), 7.57 (m, 1H), 7.45 (m, 2H), 7.25 (t, J=9 Hz, 1H), 2.23 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ5 168.79, 161.46, 148.92, 140.39, 138.59, 132.89, 128.62, 126.18, 125.28, 123.37, 120.29, 119.83, 113.05, 111.07, 25.15; IR (KBr) 3270, 1685, 1540, 1240, 750 cm-1 ; MS (DCI) m/e MH+ =253; Analysis calc' d for C15H12N2O2 : C, 71.42; H, 4.79; N, 11.10; found: C, 71.24; H, 5.14;N, 10.76.
Reaction SMILES: C([O:8][C:9]1[C:13]2[CH:14]=[N:15][C:16]([NH:18][C:19]([NH:21][C@@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[O:20])=[CH:17][C:12]=2[N:11]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[O:8]=[C:9]1[C:13]2[CH:14]=[N:15][C:16]([NH:18][C:19]([NH:21][C@@H:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:23])=[O:20])=[CH:17][C:12]=2[N:11]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:10]1
Reactant: [H][H]
Reactant: CCOC(=O)n1nc(OCc2ccccc2)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)n1[nH]c(=O)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21

Procedure:
(R)-Ethyl 3-(benzyloxy)-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (177.2 mg, 0.386 mmol) and Pd/C (4.10 mg, 0.039 mmol) were stirred in EtOAc (3.86 mL), under a balloon of hydrogen gas for 72 h. The reaction mixture was filtered through Celite, eluting with EtOAc. The filtrate was concentrated in vacuo to afford (R)-ethyl 3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate, which was carried onto the next step without further purification. MS ESI calc'd. For C18H19N5O4 [M+1]+370. found 370.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([F:32])[C:3]=1[CH2:4][NH:5][C:6]1[C:11]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].C(N(CC)CC)C.ClC1C=CC=C(F)C=1CN1C2C=CC=CC=2S(=O)(=O)N(C2C=CC(=O)N(C)C=2)C1=O>>[F:1][C:2]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([F:32])[C:3]=1[CH2:4][N:5]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:11]=2[S:12](=[O:13])(=[O:14])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:33]1=[O:34]
Reactant: COc1cc(F)c(CNc2ncccc2S(=O)(=O)Nc2ccc(OC)c(OC)c2)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cn1cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)ccc1=O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Yield: 41.9 %

Procedure:
The title compound (89 mg, 0.18 mmol) was prepared from 2-[(2,6-difluoro-4-methoxybenzyl)amino]-N-(3,4-dimethoxyphenyl)pyridine-3-sulfonamide (198 mg, 0.43 mmol), 1,1′-carbonyldiimidazole (279 mg, 1.72 mmol) and triethylamine (0.12 mL, 0.86 mmol) using the methods of (132).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[C:12]([O:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[CH:21]=[N:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([N:28]=[C:1]=[O:2])=[CH:25][CH:26]=2)[CH:21]=[N:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2cc(N=C=O)ccc21
Reaction time: 1.5 h

Procedure:
A 0° C. mixture of 1.93M solution of phosgene in toluene (8.9 mL, 17 mmol) and CH2Cl2 (80 mL) was added dropwise a solution of 5-amino-indazole-1-carboxylic acid tert-butyl ester (2 g, 8.5 mmol) and pyridine (3.5 mL, 43 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred for 1.5 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:18]>C(#N)C.C1COCC1.[Ag-]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:18])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: CI
Agent: O=[Ag-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C

Procedure:
24.1 A solution of 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 15 ml acetonitrile and 3 ml THF was treated with 3.0 g silver(I) oxide and and 2.7 ml iodomethane. The reaction mixture was stirred over night at r.t., then again treated with 3.0 g silver(I) oxide and 2.7 ml iodomethane. The reaction was agitated over night at r.t., then filtrated. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; cyclohexane/EtOAc 2:1) to give 1.0 g (3S,4S)-3-azido-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 243.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=1[CH2:27][CH2:28][CH2:29][OH:30]>>[Cl:17][C:18]1[CH:23]=[C:22]([NH:24][C:14](=[O:16])/[CH:13]=[CH:12]/[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:21]=[CH:20][C:19]=1[CH2:27][CH2:28][CH2:29][OH:30]
Reactant: O=[N+]([O-])c1ccc(CCCO)c(Cl)c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCO)c(Cl)c1

Procedure:
Prepared analogously to Intermediate product Z32a starting from (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 3-(2-chloro-4-nitro-phenyl)-propan-1-ol. The crude product was purified by column chromatography (silica gel, petroleum ether/EtOAc 1:1).
Reaction SMILES: [C:1]1(C2CCN(C([O-])=O)CC2)C=CC=CC=1.C[N:17]1[N:21]=[N:20][C:19]([C:22]2[CH:23]=[C:24]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[CH2:25][O:26][CH2:27][C:28]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[N:18]1.N1C(C2C=C(C=C(C(F)(F)F)C=2)COC[C:65]2([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[CH2:70][CH2:69][N:68]([C:71]([O:73]C(C)(C)C)=[O:72])[CH2:67][CH2:66]2)=NN=N1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:20]1[C:19]([C:22]2[CH:23]=[C:24]([CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=2)[CH2:25][O:26][CH2:27][C:28]2([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[N:18][N:17]=[N:21]1.[C:78]1([CH:65]2[CH2:66][CH2:67][N:68]([C:71]([O-:73])=[O:72])[CH2:69][CH2:70]2)[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: Cn1nnc(-c2cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3nnn[nH]3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: O=C([O-])N1CCC(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1-c1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 9 %

Procedure:
tert-Butyl 443-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-Butyl 4-((3-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate. tert-Butyl 4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (80 mg, 0.15 mmol) methyl iodide (10.0 μL, 0.15 mmol) and potassium carbonate (21.0 mg, 0.15 mmol) were combined in acetone (1.5 mL) and heated at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) afforded tert-Butyl 4-((3-(1-methyl-1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (7.0 mg, 9%) and tert-Butyl 443-(2-methyl-2H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (48 mg, 60%). Retention time: 4.75 min and 5.20 min. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=6 min., Flow rate=4 mL/min.): Mass spec.: 532.31 (MH)+ and 532.31 (MH)+ respectively.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH2:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[C:8]([Br:27])[CH:7]=1.[CH3:30][C:31]1[CH:41]=[CH:40][C:34]([CH:35]=[CH:36][C:37](O)=[O:38])=[CH:33][CH:32]=1>>[Br:27][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:28][C:37](=[O:38])[CH:36]=[CH:35][C:34]2[CH:40]=[CH:41][C:31]([CH3:30])=[CH:32][CH:33]=2)[C:3]([OH:2])=[O:29])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(Br)c1
Product: Cc1ccc(C=CC(=O)N[C@@H](Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)c(Br)c2)C(=O)O)cc1
Yield: 24 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 4-methylcinnamic acid was used in place of cinnamic acid to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-phenyl}-2-(3-p-tolylacryloylamino)-propanoic acid as a white solid with the yield of 24% and mp of 243˜245° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N:23]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:27][NH:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[CH2:27][CH2:28][N:23]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:24][CH:25]2[C:29]([O:31][CH3:32])=[O:30])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 52.6 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-yl methanesulfonate (2.4 g, 7.56 mmol), tert-butyl methyl piperazine-1,3-dicarboxylate (1.85 g, 7.56 mmol), K2CO3 (1.6 g, 11.34 mmol) in CH3CN (40 mL) was stirred at reflux for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% petroleum ether/ethyl acetate) to afford the desired product (1.85 g, 51% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=C[CH:6]=[CH:5][C:4]=1O.Cl.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:30]=3[O:29][C:27](=[O:28])[C:22]=2[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: COc1cccc(O)c1OC
Agent: Cl
Product: COc1ccc2c3c(c(=O)oc2c1OC)CN(Cc1ccccc1)CC3
Yield: 35 %

Procedure:
Prepared by the procedure of Example 1 from 2,3-dimethoxyphenol and methyl 1-benzyl-4-oxo-3-piperidine-carboxylate hydrochloride. Yield 35%; mp 138°-140° C.
Reaction SMILES: BrBr.[CH3:3][CH:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[N:8][NH:7][C:6](=[O:23])[CH2:5]1>C(O)(=O)C>[CH3:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[N:8][NH:7][C:6](=[O:23])[CH:5]=1
Reactant: CC1CC(=O)NN=C1c1ccc(-c2ccc(F)cc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]nc1-c1ccc(-c2ccc(F)cc2)cc1

Procedure:
18 g of bromine is added dropwise, with stirring, to a solution of 28.2 g of 5-methyl-6-(4'-fluoro-4-biphenyl-yl)-2,3,4,5-tetrahydropyridazin-3-one in 500 ml of acetic acid at 100°; the mixture is then heated for an additional 15 minutes at 100°, cooled and filtered. 5-Methyl-6-(4'-fluoro-4-biphenylyl)-2,3-dihydropyridazin-3-one is obtained. m.p. 245°-247°.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=4[F:47])[C:38]([CH3:48])=[C:37]([OH:49])[C:36]3=[O:50])=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:28]1[C:29]2[CH:34]=[C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=4[F:47])[C:38]([CH3:48])=[C:37]([O:49][CH3:3])[C:36]3=[O:50])[CH:32]=[CH:31][C:30]=2[N:26]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cc(Br)ccc1F
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C)C(c2cc(Br)ccc2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 g, 267.8 mmol in water), diazald (20 g, 93.37 mmol, 5 eq), ethylene glycol/Et2O (2/1 v/v, 140 mL) 1-(1H-benzo[d]imidazol-5-yl)-5-(5-bromo-2-fluorophenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (2 g, 5.57 mmol, 1 eq) and MeOH (50 mL); yield: 1.3 g (57.2%); MS m/z: 416.3 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.76 (s, 3H), 3.95 (s, 3H), 6.00 (s, 1H), 7.13 (m, 1.3H), 7.25-7.27 (m, 1.6 H), 7.47-7.49 (m, 1.6H), 7.47-7.52 (m, 1.5 H), 7.65 (m, 1.5H), 8.15 (s, 1H); HPLC (METHOD [A]): rt 12.55 min (98.5%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:19]#[N:20])[CH2:14][CH2:13][C:12]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].C([OH:25])C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:19](=[O:25])[NH2:20])[CH2:10][CH2:11][C:12]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(C#N)CCC3(CC2)OCCO3)c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C2(C(N)=O)CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 3.5 g of 4-(3-methoxyphenyl)-4-cyano-1,1-ethylenedioxy-cyclohexane, 70 ml of 5 % aqueous potassium hydroxide and 70 ml of ethanol is refluxed for 22 hours. After cooling, the mixture is diluted with water, and then extracted with chloroform. The chloroform extract is dried and evaporated to remove solvent. The residue thus obtained is recrystallized from a mixture of ethylacetate and n-hexane. 2.32 g of 4-(3-methoxyphenyl)-4-carbamoyl-1,1-ethylenedioxy-cyclohexane are obtained. M.p. 135° - 138°C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]([CH2:25][CH2:26][O:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[S:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=2[CH3:24])(=[O:14])=[O:13])[CH2:10][CH2:9]1>ClCCl>[CH:8]1([N:11]([CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])[S:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=2[CH3:24])(=[O:14])=[O:13])[CH2:9][CH2:10]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C2CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (13 eq) was added dropwise to a solution of tert-butyl 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)ethoxy)acetate in dichloromethane (10 ml/mmol) at 0° C. and the resulting solution was stirred for 2 h at 25° C. The mixture was concentrated completely and traces of trifluoroacetic acid removed under high vacuum. The crude product was used directly in the next stage with no further processing.
Reaction SMILES: C([CH:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C=C.[NH:29]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][C:34]([C:11]3[N:12]=[C:13]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[C:8]4[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:4][C:9]=4[N:10]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: C=CCC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc3[nH]ccc3c2)nc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
Compound fm was prepared according to the procedure described in Example 2 step 2 by reacting tert-butyl 8-allyl-2-chloro-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with 1H-indol-5-ylboronic acid. LC-MS: m/z=+450 (M+H)−.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:4]=[N:3][CH:2]=1.[CH3:12]O.Cl>O1CCOCC1>[N:1]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][CH:2]=1
Reactant: O=C(O)C=Cc1cncnc1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cncnc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
3-(5-Pyrimidyl)acrylic acid (100 g) was added to a mixture of dry methanol (2 L) and 4M hydrogen chloride in dioxan (445 ml) and allowed to stir at 60° C. under argon for 18 h. The mixture was cooled, and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and was washed with saturated sodium bicarbonate (300 ml). The aqueous layer was extracted with dichloromrethane and the combined dichloromethane layers were dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(5-pyrimidinyl)acrylate (85 g). 1H-NMR (d6-DMSO) δ 3.82(3H, s), 7.03(1H, d), 7.75(1H, d) and 9.28(3H, s).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([O:1][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][N:6]=1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cnc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(OS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A mixture of 3.34 g (22 mmol) methyl 5-hydroxypyrazine-2-carboxylate (commercially available), 2.73 g (24 mmol) methane sulfonyl chloride and 3.29 g (33 mmol) NEt3 in 40 mL DCM was stirred at room temperature for 4 h. Water and Na2CO3 was added and the organic layer was separated and dried with MgSO4. Evaporation yielded 3.7 g (73%) of the title compound which was used without further purification. 300-MHz-1H-NMR (DMSO): δ=9.06 (d, J=1.2 Hz, 1H, 3-H), 8.83 (d, J=1.2 Hz, 1H, 6-H), d=3.97 (s, 3H, OMe), 3.74 (s, 3H, SO2Me).
Reaction SMILES: [OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.S(=O)(=O)(O)O.[CH2:41](O)[CH3:42]>>[OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH2:41][CH3:42])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1
Reactant: CCO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@]3(O)CC[C@@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1CC[C@@](O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (100 mg, 0.197 mmol) was dissolved in ethanol (3 ml) and concentrated sulfuric acid (10.52 μl, 0.197 mmol) added. The reaction mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (3×) and washed with saturated aqueous sodium bicarbonate. Solvent evaporation gave the title compound (88 mg, 0.165 mmol, 83% yield). ESI: [M+H]+ m/z 535.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.82 (d, J=4.9, 1H), 7.93 (d, J=9.6, 2H), 7.46 (s, 1H), 7.27 (d, J=4.9, 1H), 7.14 (s, 1H), 4.07 (dt, J=10.8, 17.9, 2H), 2.31 (s, 3H), 2.05 (s, 3H), 1.96-1.78 (m, 3H), 1.65 (m, 2H), 1.18 (m, 3H), 1.09 (s, 3H), 0.97 (s, 3H). rhSYK activity=+++