Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[CH:11][N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.7 %

Procedure:
To a suspension of tert-butyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]carbamate (56 mg, 0.128 mmol) in CH2Cl2 (2 mL) at room temperature, under nitrogen, was added trifluoroacetic acid (0.197 mL, 2.56 mmol). The mixture was stirred at room temperature for 17 hours and concentrated to dryness. The residue was partitioned between ethyl acetate and 5% NaHCO3. The aqueous layer was extracted twice with ethyl acetate and the combined organic fractions were washed with water and brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (ethyl acetate/dichloromethane) to afford N-[3-(2-amino-1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (30.1 mg, 69.7%) as a beige solid. APCI [M+H]+ m/z 338.1 1H NMR (400 MHz, Acetone-d6): δ 9.21 (br s, 1H); 8.82 (d, J=4.9 Hz, 1H); 8.12 (s, 1H); 7.67 (d, J=8.2 Hz, 1H); 7.37 (s, 1H); 7.33 (t, J=8.0 Hz, 1H); 7.24 (d, J=4.9 Hz, 1H); 7.18 (d, J=7.8 Hz, 1H); 6.48-6.41 (m, 2H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:20][N:21]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C>ClCCl.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:20][N:21]=[C:11]3[CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCCCCCCc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)NC2
Yield: 25.9 %

Procedure:
6-(4-Chlorophenyl)-1-undecyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (1.23 g) was dissolved in dichloromethane (10 ml) and acetic acid (5 ml) and zinc powder (540 mg) were added thereto with stirring. After stirring at room temperature for 6 hours, the mixture was washed with 5% aqueous sodium hydrogencarbonate and water. The reaction mixture was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the oily substance obtained was crystallized from ethyl acetate to give 320 mg of 6-(4-chlorophenyl)-1-undecyl-4H,5H,6H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, mp. 94°-95° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1.[NH4+].[Cl-]>C1COCC1.O>[Cl:10][C:11]1[N:12]=[N:13][C:14]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)CCO
Reactant: Clc1ccc(Cl)nn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOc1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(Trimethylsilyl)ethanol (5.05 mL, 35.2 mmol) was taken up in THF (50 mL) and cooled to 0° C. Sodium hydride (1.48 g, 36.9 mmol) was added in 3 portions and the resulting mixture stirred at 0° C. for 15 minutes. This suspension was then added to a solution of 3,6-Dichloropyridazine (5 g, 33.6 mmol) in THF (50 mL) at 0° C. After stirring at 0° C. for 30 minutes, room temperature was attained and stirring continued overnight. Water was added followed by saturated NH4Cl and the reaction mixture was extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (2-20% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])=[CH:12][CH:11]=1
Reactant: NCCCCc1ccc(O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of 4-(4-aminobutyl)phenol hydrobromide 6 (8.2 g, 33.5mmol), phthalic anhydride 7 (5.0 g, 33.8 mmol), and triethylamine (4.6 mL, 33.5 mmol) in chloroform (50 mL) was stirred at reflux for 18 h, cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in acetic acid (50 mL) and stirred at 100° C. for 3 h. Solvent was evaporated and the resulting residue was purified by flash silica gel column chromatography eluting with CH2Cl2/EtOAc/hexanes (8:1:1, v/v) to give the desired product 8 as a white powder (4.1 g, 41% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.57 (m, 4H), 2.46 (m, 2H), 3.58 (m, 2H), 6.64 (d, 2H), 6.95 (d, 2H), 7.82 (m, 4H), 9.12 (s, 1H). m/z (ESI): 296 [C18H17NO3+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][C:19]=1[CH2:27][NH2:28].CCN(C(C)C)C(C)C>CC(O)C>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][C:19]=1[CH2:27][NH:28][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[NH:12][N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cc2cc[nH]c2cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc2[nH]ccc2cc1CNc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A sealed vial was charged with 53 (80 mg, 0.34 mmol), 244 (45 mg, 0.25 mmol), DIPEA (100 mg, 0.75 mmol), and IPA (3.0 mL). The reaction mixture was heated at 120° C. for 18 h. The solution was concentrated and purified by preparative HPLC to afford 40 mg (42%) of I-93 as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[C:5]2[OH:16].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=[C:5]2[O:16][CH2:17][CH3:18]
Reactant: CCI
Reactant: CC(=O)Nc1cc(O)c2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(NC(C)=O)nc2ccc(Br)cc12
Yield: 79.4 %

Procedure:
A mixture of N-(6-bromo-4-hydroxy-quinolin-2-yl)-acetamide (32 g, 0.114 mol), ethyl iodide (26.77 g, 0.171 mol) and potassium carbonate (130 g, 0.912 mol) in acetonitrile (250 ml) was refluxed for 2 h. The solvent was evaporated and the residue was triturated with water. The precipitate was collected by filtration and dried to afford N-(6-bromo-4-ethoxy-quinolin-2-yl)-acetamide as a pale yellow solid (28 g, 80%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH:14](=O)[C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1>C(Cl)(Cl)Cl>[CH3:19][O:18][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:20]=1[O:21][CH3:22])[CH:14]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(CN)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=NCC(OC)OC)cc1OC
Temperature: 25 °C

Procedure:
Aminoacetaldehyde dimethylacetal (11 mL, 10.73 g, 0.102 mol) was dissolved in chloroform (50 mL) and MgSO4 (8.5 g) was added. Then veratraldehyde (10a, 9.22 g, 0.055 mol) was added and the mixture was stirred at room temperature. After 24 h the MgSO4 was filtered out and the filtrate was washed with water (200 mL), brine (200 mL), dried (Na2SO4) and concentrated to provide the imine, a light yellow liquid (13.90 g, 100%). 1H NMR (300 MHz, CDCl3) δ8.09 (s, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.07 (dd, J1=1.8 Hz, J2=8.3 Hz 1H), 6.77 (d, J=8.1, 1H), 4.57 (t, J=5.1 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 31H), 3.65 (dd, J1=5.1 Hz, J2=1.2 Hz, 2H), 3.32 (s, 6H).
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]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35]>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:35]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and 2-fluoro-phenylhydrazine according to the method described for example 43. MS: M=431.1 (M+H)+
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][C@H:27]([C@@H:29]1[C@:47]2([CH3:48])[C@H:32]([C@H:33]3[C@H:44]([CH2:45][CH2:46]2)[C@:42]2([CH3:43])[C:36]([CH2:37][C@H:38]([CH2:40][CH2:41]2)O)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH3:23].OS(O)(=O)=O>C(Cl)Cl>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][C@@H:38]1[CH2:37][C:36]2[C@@:42]([CH3:43])([C@@H:44]3[C@@H:33]([CH2:34][CH:35]=2)[C@@H:32]2[CH2:31][CH2:30][C@H:29]([C@@H:27]([CH2:26][CH2:25][CH2:24][CH:22]([CH3:21])[CH3:23])[CH3:28])[C@@:47]2([CH3:48])[CH2:46][CH2:45]3)[CH2:41][CH2:40]1)=[O:19]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
DCPLA (1 g), cholesterol (1 g), CH2Cl2 (20 ml), and concentrated H2SO4 (1 μl) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the DCPLA-cholesteryl ester. Linoleic acid (1 g), cholesterol (1 g), CH2Cl2 (20 ml), and concentrated H2SO4 (20 μl) were combined and refluxed overnight. The product was washed with sodium phosphate (pH 7.0, 5 ml) and purified by flash chromatography to yield the cholesteryl linoleate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])=[C:4]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[CH:3]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C@@H:10]([NH:12][C:13]3[N:21]=[CH:20][N:19]=[C:18]4[C:14]=3[N:15]=[CH:16][NH:17]4)[CH3:11])[N:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[C:4]=2[CH:3]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)C(=S)Nc1ccc(F)cc1Nc1ccncn1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccncn1
Yield: 93.2 %

Procedure:
(S)—N-[4-Fluoro-2-(pyrimidin-4-ylamino)phenyl]-2-(9H-purin-6-ylamino)thiopropionamide (9 mg, 0.02 mmol) was heated in toluene at reflux under nitrogen for 15 h. The reaction mixture was purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 332 as a colourless solid, (7 mg, 85%). LCMS (Method C): RT 2.82 min [M+H]+ 376.02 1H NMR (DMSO-d6) δ: 12.8 (1H, bs), 9.20 (1H, s), 8.95 (1H, d, J=5.41 Hz), 8.01-7.89 (4H, m), 7.73 (1H, dd, J=8.81, 4.94 Hz), 7.46 (1H, dd, J=9.30, 2.50 Hz), 7.18 (1H, td, J=9.27, 2.48 Hz), 6.03 (1H, bs), 1.71 (3H, d, J=6.78 Hz)
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:22][C:20]1[CH:19]=[C:18]([C:23]2([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26][N:25]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=3)[CH2:24]2)[CH:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: COC(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To the solution of methyl 4-fluoro-2-nitrobenzoate (1.1 g) and 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.5 g) in 1-methyl-2-pyrrolidinone was added potassium carbonate (1.5 g) and the mixture was heated with stirring at 100° C. for two hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield methyl 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoate (1.24 g). 1H-NMR (CDCl3) δ: 2.53-2.67 (1H, m), 2.89-2.97 (1H, m), 3.50-3.71 (2H, m), 3.83 (1H, d), 3.85 (3H, s), 4.15 (1H, d), 6.69 (1H, dd), 6.75 (1H, d), 7.26 (2H, d), 7.42 (1H, t), 7.81 (1H, d)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[N:19]1[CH:20]=[CH:21][C:16]([NH:15][C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: Nc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc2oc(Nc3ccncc3)nc12
Temperature: 90 °C

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (350 mg, 1.65 mmol), 4-aminopyridine (233 mg, 2.48 mmol), palladium(II) acetate (7.4 mg, 0.033 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (39 mg, 0.083 mmol), K2CO3 (570 mg, 4.13 mmol) and t-BuOH (4 mL) was heated to 90° C. for 40 min. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 CH2Cl2/CH3OH) to afford methyl 2-(pyridin-4-ylamino)benzoxazole-4-carboxylate. 1H NMR and MS consistent.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:24])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[N:17]2)[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH:27]1([C:30]2[S:31][C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:33]([C:35](Cl)=[O:36])[N:34]=2)[CH2:29][CH2:28]1>C1COCC1.O>[C:3]([O:7][C:8](=[O:24])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[N:17]2)[O:13][CH:14]=1)[C:35]([C:33]1[N:34]=[C:30]([CH:27]2[CH2:28][CH2:29]2)[S:31][C:32]=1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:36])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)c1ccn(Cc2nc(NC(=O)OC(C)(C)C)co2)n1
Reactant: O=C(Cl)c1nc(C2CC2)sc1-c1ccccc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccn(Cc2nc(N(C(=O)OC(C)(C)C)C(=O)c3nc(C4CC4)sc3-c3ccccc3)co2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-pyrazol-1-ylmethyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (76 mg, 0.25 mmol) in THF (1.0 mL) was added to a suspension of NaH (27 mg, 0.61 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-cyclopropyl-5-phenyl-thiazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.11 min, [M+H]+=534.30.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][S:32][C:33]1[CH:34]=[C:35]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=23)=[O:40])[CH:36]=[N:37][CH:38]=1)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][S:32][C:33]1[CH:34]=[C:35]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])[S:46][C:45]=23)=[O:40])[CH:36]=[N:37][CH:38]=1)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(SCCN=[N+]=[N-])c3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(SCCN=[N+]=[N-])c5)c4s3)[C@H](C)[C@H]12
Yield: 41 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[5-(2-azidoethylthio)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (370 mg) was prepared in the same manner as in step a) of Example 1, except that 485 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 857 mg of 7-[5-(2-azidoethylthio)pyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.Br[CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31].FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=NN4CC(O)=O)=CC=3)=CC=2)=C(OC)C=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][N:23]4[CH2:35][CH2:29][C:30]([OH:32])=[O:31])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cn[nH]c3c2)cc1
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cnn(CC(=O)O)c3c2)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cnn(CCC(=O)O)c3c2)cc1

Procedure:
3-[6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid was prepared from 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.1 g, 0.221 mmol) and ethyl bromopropionate (40 mg, 0.221 mmol), as described above for [6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic acid, to yield 81 mg (83.6%) of product. LC-MS (ES) calculated for C24H20F2N2O4, 438.43; found m/z 439 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([C:16]3[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)[CH3:15])[CH2:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[Cl-].Cl[CH2:27][CH2:28][NH+:29]([CH3:31])[CH3:30]>CC(N(C)C)=O>[CH:1]1([N:4]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:5]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][N:14]([C:16]3[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)[CH3:15])[CH2:11][CH2:12]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CN(C[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1ncc(Br)cn1
Reactant: C[NH+](C)CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)CCN(C(=O)[C@H]1CC[C@H](CN(C)c2ncc(Br)cn2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
0.12 g (0.33 mmol) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropylamide was dissolved in 10 mL of DMA and treated with 0.21 g (4.90 mmol, 14 eq) of NaH (55% in oil) at 0° C. then warmed to RT. The mixture was then treated with 0.47 g (3.27 mmol, 10 eq) of N-(2-chlorethyl)-N,N-dimethylammonium chloride at 0° C. and warmed to RT. The reaction was stirred for 27 h, then partitioned between Et2O (×3)/aqueous 10% NaHCO3, washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel (20g) with CH2Cl2:MeOH 95:5 to yield 0.09 g (68% over 2 steps) of pure trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropyl-(2-dimethylamino-ethyl)-amide, MS: 438 (MH+, 1Br).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22]C=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=C[N:43]3[C:56](=[O:57])[N:55]([CH3:58])[N:54]=C3C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][N:43]5[C:56](=[O:57])[N:55]([CH3:58])[N:54]=[C:22]5[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: Cn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Product: Cn1nc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccn2c1=O
Yield: 61 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-2-methyl-8-phenyl-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione was reacted to give the title compound as a colourless gum (19.9 mg, 61%). LCMS (Method A): RT=4.63 min, [M+H]+=539.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6]2.[CH2:15]([OH:17])C>[Pd]>[CH3:15][O:17][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCCC1C=Cc2cc(OC)ccc21
Agent: [Pd]
Product: CCCC1CCc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
The mixture of indenes from step 1 (1.24 g, approx. 6.1 mmol) was dissolved in ethanol (40 mL), treated with 10% Pd on carbon (58 mg), and hydrogenated at 40 psi and room temperature for 60 minutes. The catalyst was removed by filtration and the filtrate was evaporated under vacuum to provide a mixture (1.287 g) of 6-methoxy-1-propyl-indan and 5-methoxy-1-propyl-indan in nearly a 1:1 ratio.