Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:8]([C:9](=[O:22])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.[NH+]1C=CC=CC=1>O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:8]3[C:9](=[O:22])[CH:10]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: COc1ncccc1C(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=c1cc(-c2ccc([N+](=O)[O-])cc2)oc2ncccc12
Temperature: 190 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
1-(2-methoxy pyridine-3-yl)-3-(4-nitrophenyl) propane-1,3-dione (2.16 g, 7.193 mmol) and pyridinium hydrochloride (12.47 g, 107.9 mmol) were mixed together and stirred at 190° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to rt. Water (100 mL) was added, the solid was separated by filtration, washed with water and dried under vacuum. The crude compound was purified by column chromatography (SilicaGel 230-400 mesh; 2-5% methanol in CH2Cl2 as eluent) to give 2-(4-nitrophenyl)-4H-pyrano[2,3-b]pyridine-4-one as a brown solid in 43% yield (0.82 g). MS (ES) m/z: 268.88 (M); Mp. 261-263° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].Cl[C:10]([O:12][CH3:13])=[O:11].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2]
Reactant: COC(=O)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(CCCl)CCCl

Procedure:
The starting material N,N-bis-(2-chloroethyl)-carbamic acid methyl ester is prepared by treating a solution of bis-(2-chloroethyl)-amine hydrochloride in methylene chloride at 0° C. with methyl chloroformate (1.0 mole equivalent) and diisopropylethylamine (2.2 mole equivalents).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][C:25]#[C:26][Mg]Br>>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[O:14])[C:26]#[C:25][CH2:24][O:23][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: Br[Mg]C#CCOC1CCCCO1
Reactant: CCc1c(OC)nc2nc(C=O)cn2c1C
Product: CCc1c(OC)nc2nc(C(=O)C#CCOC3CCCCO3)cn2c1C

Procedure:
6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-carboxaldehyde and 3-(tetrahydropyran-2-yloxy)-1-propynylmagnesium bromide [J. Chem. Soc., 1950, 3646] were reacted by the method of Step A of Example 1 to obtain 1-(6-ethyl-7-methoxy-5-methylimidazol[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one.
Reaction SMILES: [Li+].[Br-].[BH4-].[Na+].[O:5]=[C:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:15][C:16](OCC)=[O:17])[CH:12]=2)[NH:7]1.B(OC)(OC)OC.[Na+].[Cl-]>C1COCC1.OS(O)(=O)=O>[OH:17][CH2:16][CH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:5])[CH2:14]2
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(=O)N2
Agent: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: O=C1Cc2cc(CCO)ccc2N1

Procedure:
LiBr (1.03 g) is added to a solution of NaBH4 (0.45 g) in THF (15 ml). The reaction mixture is heated at reflux for 7 hours, and the compound obtained in Step B (1.3 g) is added, followed by B(OMe)3 (0.067 ml). After refluxing for 18 hours, the mixture is concentrated under reduced pressure and the residue obtained is taken up in 20 ml of 3N H2SO4. The aqueous phase is saturated with NaCl and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness. The residue is purified on silica gel (SiO2, eluant: AcOEt) to yield the title product in the form of a beige solid. The compound obtained is used directly in the next reaction.
Reaction SMILES: [NH:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH2:2].[CH:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[CH:10][CH:9]=1>C(O)C>[C:11]1(/[CH:14]=[CH:15]/[CH:16]=[N:2]/[NH:1][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)N/N=C/C=C/c1ccccc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 5a (4.00 g, 38.4 mmol) and trans cinnamic aldehyde (7.60 g, 57.5 mmol) in ethanol (100 ml) was heated under reflux for 3 h. After cooling to room temperature, the mixture was filtered, and the residue dried under vacuum to give 6.77 g of a white solid. Refiltration of the filtrate gave another 0.73 g of the residue and an overall yield of 91%.
Reaction SMILES: [CH3:1][O:2][C:3]1([NH:36][C:37](=[O:46])[CH:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[OH:39])[C:34](=[O:35])[N:5]2[C:6]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:7]([CH:10]([S:12][C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH3:11])[CH2:8][S:9][C@H:4]12>C1COCC1.C(O)=O>[CH3:1][O:2][C:3]1([NH:36][C:37](=[O:46])[CH:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[OH:39])[C:34](=[O:35])[N:5]2[C:6]([C:18]([OH:20])=[O:19])=[C:7]([CH:10]([S:12][C:13]3[NH:14][N:15]=[N:16][N:17]=3)[CH3:11])[CH2:8][S:9][C@H:4]12
Reactant: COC1(NC(=O)C(O)c2ccccc2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@@H]21
Solvent: C1CCOC1
Solvent: O=CO
Product: COC1(NC(=O)C(O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C

Procedure:
The ester, 100 mg. was dissolved in 1 ml of a 50:50 mixture of THF and 97% formic acid at 0° C. The mixture was allowed to warm to room temperature and was then evaporated to dryness. Ethyl acetate was added to dissolve the residue and the solution was extracted twice with a saturated solution of sodium bicarbonate. The bicarbonate extracts were combined and were then acidified with dilute hydrochloric acid to pH 2.5. The product was extracted from the acidified bicarbonate extracts with ethyl acetate. The ethyl acetate was dried and evaporated to yield 53 mg of product, 7-methoxy-7-mandelamido-3-(1-methyltetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid having the following NMR spectrum (60 megacycles run in acetone d6)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[C:21]([C@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[C:22]([O:25][CH3:26])=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C.C(O)CCC>CCOC(C)=O>[F:18][C:19]1[CH:20]=[C:21]([C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:22]([O:25][CH3:26])=[N:23][CH:24]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: COc1ncc(F)cc1[C@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Yield: 56.3 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.75 g, 3.32 mmol), (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine dihydrochloride (0.984 g, 3.66 mmol), diisopropylethylamine (2.32 mL, 13.3 mmol) and n-butanol (1.11 mL) were heated at 90° C. for 48 hours. The reaction mixture was diluted with EtOAc and the mixture was washed with water, brine and saturated NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated afford a dark orange oil. The oil was purified by silica chromatography, eluting with a 50-80% EtOAc/Hexane gradient, to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.72 g, 56.2%) as a yellow foam. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[C@@H:8]([OH:16])[CH2:7]1)=O.[CH2:19](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)[CH:20]=[CH2:21]>>[CH2:21]([O:16][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C@@H:6]([NH2:5])[CH2:7]1)[CH:20]=[CH2:19]
Reactant: Cc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Product: C=CCO[C@@H]1C[C@H](N)c2cc(C)ccc21
Yield: 75 %

Procedure:
Step BK (2): The product from Step BK (1) was N-deprotected by a procedure analogous to Step U (2) to afford 480 mg (75% yield) of (1S,3R)-3-(allyloxy)-6-methyl-2,3-dihydro-1H-inden-1-amine as a white solid. LC-MS (M+H)+=204.13 1H NMR (500 MHz, CDCl3) δ ppm 7.28 (d, 1H) 7.18 (d, 1H) 7.08 (d, 1H) 6.01-5.94 (m, 1H) 5.32 (d, 1H) 5.18 (d, 1H) 4.77 (t, 1H) 4.16-4.19 (m, 3H) 2.80-2.75 (m, 1H) 2.36 (s, 3H) 1.75-1.70 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([S:16](=[O:26])(=[O:25])[NH:17]C(OC(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH3:15]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([S:16](=[O:25])(=[O:26])[NH2:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COC(=O)CN(c1ccc(OC)cc1OC)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(OC)cc1OC)S(N)(=O)=O

Procedure:
A solution of 1.7 g (4.2 mmol) of the title B compound, N-(t-butoxycarbonyl-sulfamoyl)-N-(2,4-dimethoxyphenyl)glycine methyl ester in 9 mL of TFA/CH2Cl2 (1:1) is stirred at RT for 30 min. The solvent is removed under reduced pressure. CH2Cl2 is added to the residue and the solvent is removed under reduced pressure. The resulting oil is purified by chromatography using 10% EtOAc in CH2Cl2 as the eluant to afford N-sulfamoyl-N-(2,4-dimethoxyphenyl)glycine methyl ester as an oil which crystallizes on standing: mp=100-103° C.; 1H-NMR (CDCl3) δ 7.50 (d, J=8.09, 1H), 6.51-6.44 (m, 2H), 4.98 (br s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][CH2:40][C@@H:41]([CH3:44])[CH2:42][OH:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:43][CH2:42][C@H:41]([CH3:44])[CH2:40][CH2:39][NH:38][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]1)=[O:36]
Reactant: C[C@@H](CO)CCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)CCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 64.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.16 g, 0.29 mmol) was reacted with (R)-4-amino-2-methyl-1-butanol (TCI-US) (0.1 g, 1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide as a white solid (0.1 g, 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[F:17][CH:18]([F:22])[CH2:19][O:20][NH2:21]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:21][O:20][CH2:19][CH:18]([F:22])[F:17])[N:3]=1)[CH2:14][CH3:15]
Reactant: NOCC(F)F
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(NOCC(F)F)n1
Yield: 59 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-(2,2-difluoro-ethyl)-hydroxylamine hydrochloride as described in Example 13, affording C in 59% yield. 400 MHz 1H NMR (DMSO-d6, ppm) 9.91-9.56 (1H, m), 7.00-6.90 (1H, m), 6.89-6.67 (1H, m), 6.48-6.13 (1H, m, 4.12-3.98 (2H, m), 3.20-3.09 (4H, m), 1.53-1.41 (4H, m), 0.88-0.80 (6H, m). ESI-MS (m/z) 291 [M+H]+.
Reaction SMILES: C([NH:8][C@@H:9]([C@@H:13]([O:15][CH3:16])[CH3:14])[C:10](O)=O)(OC(C)(C)C)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:10]([C@@H:9]([NH2:8])[C@@H:13]([O:15][CH3:16])[CH3:14])=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CO[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CO[C@@H](C)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using N-boc-(2S,3S)-2-amino-3-methoxybutanoic acid and 4-tert-butyl-1,2-diaminobenzene.
Reaction SMILES: [CH2:1]([N:5]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([C:30]([CH3:32])=[CH2:31])=[CH:25][N:24]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([N:5]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH:30]([CH3:32])[CH3:31])=[CH:25][N:24]=1)[S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH:2]([CH3:4])[CH3:3]
Reactant: C=C(C)c1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Yield: 73.6 %

Procedure:
N-isobutyl-N-(3-methyl-5-(prop-1-en-2-yl)pyridin-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (83 mg, 0.18 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL). The reaction was hydrogenated using an H-cube flow hydrogenator (settings: room temperature, 1 bar, 1 mL/min flow rate) and a 10% Pd/C CatCart as the catalyst. Two clean fractions of product were collected along with a third impure fraction, the impure fraction was then purified by mass directed autoprep (formic acid modifier). The two clean product fractions and purified third fraction were then combined and evaporated to give the title compound (61 mg). LCMS (2 min, formic) Rt 1.45 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([CH2:14][CH:15]([C:21]1([CH3:26])OCC[O:22]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:13])([O-:3])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([CH2:14][CH:15]([C:21](=[O:22])[CH3:26])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C(C)=O

Procedure:
Ethyl 2-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (116 mg, 22%) in the same manner as described in the above example 6 (20) from ethyl 3-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.38 g, 1.58 mmol) and p-toluenesulfonic acid monohydrate (25 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24].C(=O)([O-])[O-].[K+].[K+].O>C(O)(=O)C>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of acetic acid were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate. The reaction was carried out for 3 hours with stirring at 15°-20.C. Thereafter 75.3 g of water was added and the mixture was stirred for one hour at 15°-20.C. The precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-phenylalanine methyl ester. Analysis of HPLC revealed that the crystals had an α-isomer:β-isomer ratio of 99.6:0.4. The yield of the α-isomer was 28.6 g. In the filtrate, 7.2 g of the α-isomer and 6.2 g of the β-isomer were present.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[N:10]=[CH:11][C:12]3[N:13]([CH:24]=[N:25][CH:26]=3)[C:14]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[F:23])=[O:8])[CH2:3][CH2:2]1.COC(C1N=CC2N(C=NC=2)C=1NC1C=CC([Br:44])=CC=1F)=O>>[Br:44][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[N:13]3[CH:24]=[N:25][CH:26]=[C:12]3[CH:11]=[N:10][C:9]=2[C:7]([NH:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:8])=[C:17]([F:23])[CH:18]=1
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Reactant: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(I)cc1F
Product: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(Br)cc1F

Procedure:
The title compound was prepared in an analogous fashion to N-(cyclopropylmethoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide, using 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester as the starting material. 1H NMR (MeOD, 400 MHz) δ ppm 8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.48 (dd, J=10.4 Hz, 3.2 Hz, 1H), 7.30 (d, 8.4 Hz, 1H), 6.75 (t, J=8.4 Hz, 1H), 3.79 (d, J=7.2 Hz, 2H), 1.26-1.13 (m, 1H), 0.62-0.55 (m, 2H), 0.36 to 0.30 (m, 2H); LCMS (method D1): RT=0.985 min, [M+H]+=420/422.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][N:7]=[C:6]2[NH:14][CH:15]([CH3:17])[CH3:16].CN(C)C=O>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[OH:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][CH:15]([CH3:17])[CH3:16])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:2]=[O:1]
Reactant: CC(C)Nc1ncnc2cc(O)c(CO)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Nc1ncnc2cc(O)c(C=O)cc12
Yield: 56 %

Procedure:
6-(Hydroxymethyl)-4-(isopropylamino)quinazoline-7-ol (510 mg, 2.19 mmol) is dissolved in 50 mL of toluene and 5 mL of dimethylformamide and at room temperature admixed portionwise with manganese(IV) oxide (1.9 g, 21.9 mmol). After 24 hours the batch is filtered through Celite and washed with dichloro-methane/methanol 9/1. Removal of the solvent and also chromatographic purification (silica gel, dichloromethane/methanol: 0→50% methanol) gives the desired product in 56% yield (280 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([O:9][C@H:10]2[C@@:15]([OH:17])([CH3:16])[C:14]([CH3:19])([CH3:18])[O:13][C:12]3[CH:20]=[CH:21][C:22]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[C:29]([O:35]C)[CH:28]=4)(=[O:26])=[O:25])=[CH:23][C:11]2=3)=[N:3]1.O>ClCCl.B(Br)(Br)Br>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([O:9][C@H:10]2[C@@:15]([OH:17])([CH3:16])[C:14]([CH3:19])([CH3:18])[O:13][C:12]3[CH:20]=[CH:21][C:22]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:35])[CH:28]=4)(=[O:26])=[O:25])=[CH:23][C:11]2=3)=[N:3]1
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H](Oc2ccc(=O)n(C)n2)[C@](C)(O)C(C)(C)O3)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)c(O)c4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
(3S,4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-6-(3,4-dimethoxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.50 g) (see Preparation 26) was dissolved in dichloromethane (12 ml) (under a nitrogen atmosphere) and boron tribromide (4 ml of a 1 M solution in dichloromethane) was added. The mixture was stirred at room temperature for one hour and a precipitate was formed. Water (20 ml) and dichloromethane (15 ml) were added, an insoluble gum formed and the solvents were decanted off. The gum was then chromatographed on silica using 1:9 methanol:dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-6-(3,4-dihydroxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.33 g) as a white foam which was then triturated with diethyl ether and dried to give a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH2:33][CH2:34][OH:35])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C(OCC)(=O)C>[CH3:8][S:9]([O:35][CH2:34][CH2:33][C:29]1[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:23][CH:22]=2)[CH:32]=[CH:31][N:30]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)Oc1ccc(CCCCn2ccnc2CCO)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2CCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (3.16 ml) and methanesulfonyl chloride (1.40 ml) were added to a solution of 2-[1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]ethanol (4.77 g) in ethyl acetate (50 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 2-[1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]ethyl methanesulfonate. Sodium thiomethoxide (2.25 g) was added to a solution of the product in DMF (35 ml), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:3) to give the titled compound (4.22 g) as a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C1C=CC=CC=1.[ClH:23].CO>>[ClH:23].[F:22][C:19]1[CH:18]=[CH:17][C:16]([N:11]2[CH2:10][CH:9]3[CH2:15][CH2:14][CH:12]2[CH2:13][NH:8]3)=[CH:21][CH:20]=1
Reactant: Fc1ccc(N2CC3CCC2CN3Cc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(N2CC3CCC2CN3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Benzyl-5-(4-fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]octane (1.1 g, 3.71 mmol) was dissolved in 1N hydrochloric acid/methanol (60 mL) and under nitrogen 10% palladium on carbon (0.50 g) was added. The reaction was hydrogenated at 1 atmosphere for 2 hours. The reaction was filtered through Celite and concentrated to yield 2-(4-Fluoro-phenyl)-2,5-diaza-bicyclo[2.2.2]octane, hydrochoride salt (0.90 g, 100%) as an off white solid which had the following properties: Mp. 154-156° C.; 1H NMR CDCl3 δ: 9.74 (brd s, 1H), 9.67 (brd s, 1H), 7.00 (t, J=9.1 Hz, 2H), 6.68-6.61 (m, 2H), 4.07 (s, 1H), 3.70 (brd s, 1H), 3.63 (d, J=11.2 Hz, 1H), 3.29 (d, J=10.8 Hz, 1H), 3.23 (brd s, 2H), 2.19-2.04 (m, 1H), 1.95-1.83 (m, 1H), 1.81-1.64 (m, 2H).