Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(CC)C(O)=[O:4].[CH3:8][CH:9]([CH2:24][CH3:25])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11].O.C(=O)([O-])O.[Na+]>CO>[OH:4][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH:9]([CH3:8])[CH2:24][CH3:25])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCC(C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 87.9 %

Procedure:
0.67 g of the above 2-methylbutanoic acid-4-(2-methylbutanoyl) biphenyl was mixed with 95 ml of methyl alcohol and 5 ml of water and added with 1.14 g (13.6 mmol) of sodium hydrogen carbonate with stirring, which was subjected to hydrolysis reaction at room temperature for 40 hours. After the completion of the reaction, methanol was distilled off and 1 normal hydrochloric acid was added to adjust pH to not more than 1, and the extraction with dichloromethane was performed. The extracted liquid was washed with water, dried on anhydrous sodium sulfate and purified by a column chromatography of silica gel after the removal of the solvent to obtain 0.44 g (yield 88%) of (+)-4-hydroxy-4'-(2-methylbutanoyl) biphenyl at a light yellow crystal having the aforementioned properties.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:11][O:10][C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[F-:18].[K+].CS(C)=O>O>[F:18][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:11][O:10][C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: [F-]
Reactant: CO[C@H](C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H](C)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 120 °C
Yield: 87.5 %

Procedure:
To a microwe vial with stir bar was added (R)-3-(2-chloropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (145 mg, 0.56 mmol), potassium fluoride (327 mg, 5.63 mmol) and DMSO (4 mL). Vial capped and heated to 120° C. in a sand bath for 3 hr. Reaction mixture was then cooled to room temperature, diluted with water and aqueous mixture extracted with EtOAc. The Organic phases were combined and washed with water, brine, dried (Na2SO4), filtered and concentrated to afford a white crystalline of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one (117 mg, 0.49 mmol, 86% yield). LCMS m/z 242.1 (M+H)+, Rt 0.63 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.C(O)C.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH:38]([OH:41])[CH2:39][CH2:40]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(-c2csc3c(CCCN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 26.7 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (130 mg, 0.23 mmol), ethanol (25 mL), and acetic acid (0.65 mL) were combined in a hydrogenation vessel, purged, and palladium hydroxide on carbon (45 mg, 50% weight dispersion in oil, 0.16 mmol) was added. 50 Psi of hydrogen was applied for 16 hours. The mixture was filtered and purified by RP-HPLC to yield the title compound (35 mg, 25% yield) after lyophilization: 1H NMR (DMSO, 400 MHz) δ 9.50 (s, 1H), 7.98 (d, 1H), 7.70–7.72 (m, 2H), 5.59 (d, 1H), 7.54 (s, 1H), 7.07–7.35 (m, 3H), 5.34 (bs, 2H), 4.58 (bs, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 2.71 (t, 2H), 2.28 (t, 2H), 1.97 (t, 2H), 1.90 (s, 3H), 1.82 (t, 2H), 1.70 (m, 1H), 1.40 (q, 2H); RP-HPLC (Conditions i) Rt 10.0 min. MS: 568.3 MH−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH:9]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:48]1[CH:58]=[CH:57][CH:56]=[CH:55][C:49]=1[CH2:50][NH:51][C:52](=[O:54])[CH3:53]>>[C:52]([NH:51][CH2:50][C:49]1[CH:55]=[CH:56][CH:57]=[CH:58][C:48]=1[C:33]1[CH:34]=[CH:35][C:30]([CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:22]([Cl:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=3[Cl:27])=[CH:13][CH:12]=2)[CH2:8][NH:7][C:6](=[O:46])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:31]([CH3:45])[CH:32]=1)(=[O:54])[CH3:53]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: CC(=O)NCc1ccccc1Br
Product: CC(=O)NCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl{3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and N-(2-bromobenzyl)acetamide (V.13) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 100% in 15 min) afforded the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:26].[K+].[K+].Cl>O1CCOCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:6]2[N:5]=[CH:4][NH:3][C:2](=[O:26])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(/C=C/c2cc(Cl)ncn2)cc1
Reactant: O=C([O-])[O-]
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc(/C=C/c2ccc(Cl)cc2)nc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of (E)-4-chloro-6-(4-chlorostyryl)pyrimidine Part A (120 mg, 0.48 mmol), DABCO (107 mg, 0.96 mmol), and potassium carbonate (660 mg, 4.78 mmol) in Dioxane (0.4 mL) and Water (4 mL) was stirred at 60° C. overnight. The reaction was cooled to RT, acidified with 10% HCl, extracted with EtOAC, dried (Na2SO4), and concentrated. The product was triturated with DCM to afford the desired product (E)-6-(4-chlorostyryl)pyrimidin-4(3H)-one 20B (108 mg, 0.46 mmol, 97% yield) as a light yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2O)(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:23])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2ncnc(O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Temperature: 90 °C
Yield: 90 %

Procedure:
To a solution of 4-hydroxyquinazolin-6-yl acetate (12.0 g, 58.8 mmol) in thionyl chloride (50 mL) was added DMF (0.5 mL). After heating to 90° C. for 3 hours, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene to provide the product (11.8 g, 90%) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+]>O.CO>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-(3-Amino-phenyl)-3,4-dihydro-1H-benzo[h]quinolin-2-one (0.29 g, 1 mmol) was dissolved in a mixture of con. sulfuric acid (2.5 ml), water (2.5 ml) and methanol (2.5 ml). The solution was stirred at 0° C. and a solution of sodium nitrite (0.83 g, 1.2 mmol) in water (1 ml) was slowly added. The solution was stirred at 0° C. for 0.5 hr and a solution of sodium azide (0.13 g, 2 mmol) in water (1 ml) was added. The mixture was stirred at 0° C. for 0.5 hr followed by overnight stirring at ambient temperature. Water was added and the precipitate separated by filtration. The product was purified by reverse phase HPLC (0.05 g, 0.15 mmol) (water-acetonitrile gradient, 0.05% formic acid, 90:10 to 10:90, 20 min, linear gradient; flow, 15 ml/min; column, Phenomenex Luna 5μ C18, 100×21.2 mm; UV 254 and 218 nm).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC=CN=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccn3)c(-c3ccc(Cl)cc3)c2CC1
Agent: Cl
Product: Clc1ccc(-c2nn(Cc3ccccn3)c3c2CCNCC3)cc1
Yield: 7.4 %

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) using 2-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-pyridin-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H19ClN4, 338.13; found, m/z 339.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 1H), 7.56-7.54 (m, 1H), 7.44-7.42 (m, 2H), 7.32-7.30 (m, 2H), 7.19-7.11 (m, 1H), 6.84-6.82 (m, 1H), 5.39 (s, 2H), 2.93-2.87 (m, 4H), 2.76-2.74 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]([CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(C(OC(C)(C)C)=O)[C:4]([O:6]C(C)(C)C)=[O:5]>FC(F)(F)C(O)=O.C(O)(=O)C>[F:31][CH:2]([F:1])[CH:3]([CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1=O)(C(=O)OC(C)(C)C)C(F)F
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
2-Difluoromethyl-2-(2-phthalimidoethyl)-propanedioic acid, bis tert.-butyl ester prepared as in Step B (0.610 g, 1.40 mM) is dissolved in trifluoroacetic acid (8 ml) at room temperature. After stirring for 1.5 hour at room temperature, the solvent is evaporated in vacuo yielding a white solid. The crude disubstituted malonic acid is dissolved in glacial acetic acid (20 ml) and the mixture is heated at 100° C. for 15 hours. The solvent is evaporated in vacuo yielding a yellowish oil. Crystallization in ether affords the required acid as a white solid (0.240 g, yield 60%). NMR (CDCl3 +CF3CO2H) 2.00-2.43 (m, 2H); 2.57-3.40 (m, 1H); 3.90 (t, JHH =7 Hz, 2H); 6.03 (td, JHF =55 Hz, JHH =4 Hz, 1H); 7.58-7.95 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:18]S(O)(=O)=O>C(OCC)(OCC)OCC>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:1]=[CH:18][N:9]2[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:7][N:6]=1
Reactant: CS(=O)(=O)O
Reactant: Nc1cnc(Cl)nc1NCc1ccccc1F
Solvent: CCOC(OCC)OCC
Product: Fc1ccccc1Cn1cnc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6.5 g (25.7 mmol) of 5-amino-2-chloro-4-[N-(2-fluorobenzyl)-amino]-pyrimidine are dissolved at room temperature in 65 ml of triethyl orthoformate. 30 mg of methanesulfonic acid are added to the solution and the reaction mixture is then stirred for 15 hours at room temperature. The reaction mixture is then concentrated by evaporation and the residue is chromatographed on silica gel with toluene/ethyl acetate (3:1) as eluant. The eluate is concentrated by evaporation and the residue obtained is recrystallised from dichloromethane/diethyl ether. In this manner 2-chloro-9-(2-fluorobenzyl)-9H-purine is obtained in the form of colourless crystals having a melting range of from 103° to 104°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Br)[C:5]([OH:7])=[O:6].[CH3:12][N:13](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:12]#[N:13])[C:5]([OH:7])=[O:6]
Reactant: CN(C)C=O
Reactant: Nc1cc(C(=O)O)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)O)cc1N
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of 3-amino-4-bromo-benzoic acid (6.0 g, 276 mmol) in dimethyl formamide (30 ml), was added sequentially at ambient temperature zinc cyanide (11.66 g, 99.4 mmol) and tetrakis(triphenylphosphine)palladium (9.57 g, 8.28 mmol). The mixture was heated to 100° C. for 14 hours. The reaction mixture was allowed to cool to ambient temperature before the sequential addition of more zinc cyanide (0.65 g, 5.54 mmol) and tetrakis(triphenylphosphine)palladium (1.9 g, 1.64 mmol) at ambient temperature. The mixture was heated to 100° C. for 1 more hour. The reaction mixture was allowed to cool to ambient temperature and was quenched by addition of a mixture of toluene and aqueous ammonia (1M). The phases were separated and the aqueous layer was extracted with toluene. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:2 to 1:0) to give 3-amino-4-cyano-benzoic acid (2.94 g, 67% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][C:24](N=[N+]=[N-])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CC(C)=O>[C:19]([O:23][C:24]([NH:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCc1ccsc1CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccsc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 3-aminomethyl-2-thienylacetic acid 8 (3.1 g, 18 m. moles) and triethylamine (8 g. 80 m moles) in 50% aqueous acetone (80 ml) was added dropwise t-butoxycarbonyl azide (5.7 g, 40 m moles) over a period of 20 mins. at 0° C. with vigorous stirring. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The concentrate was washed with ether (2×20 ml), adjusted to pH 2 with conc. HCl and extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were washed with saturated aqueous sodium chloride, dried over MgSO4, treated with charcoal and evaporated under reduced pressure. The residue was triturated with n-hexane and crystallized from n-hexane and benzene to give 4.5 g (92%) of colorless needles 9, melting at 62°-63° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: O=c1[nH]nc(Sc2ccc(Br)cc2)c2ccccc12

Procedure:
4-chlorophthalazin-1(2H)-one and 4-bromobenzenethiol were processed using a method similar to that described in Example 57A to afford the title compound. MS (APCI) M/Z 374 (M+CH3CN)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(CCOS(C)(=O)=O)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
Methyl (3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate (Intermediate 41) (650 mg, 1.93 mmol) was reacted with methanesulfonyl chloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL, 2.7 mmol) as described for Intermediate 6. The crude product was used without delay for the next step.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2F)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2F)ccn1)NO
Reaction time: 22 h

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (30 mg, 0.07 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a white wax (15 mg, 79%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=O)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:35]([C:37]1[CH:38]=[C:39]([CH:44]=[C:45]([CH3:48])[C:46]=1[OH:47])[C:40]([NH:42]O)=[NH:41])[CH3:36]>CN(C=O)C>[CH2:35]([C:37]1[CH:38]=[C:39]([C:40]2[N:41]=[C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[C:10]([CH3:12])[CH:9]=3)[CH:1]=[O:2])[O:8][N:42]=2)[CH:44]=[C:45]([CH3:48])[C:46]=1[OH:47])[CH3:36]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)cc(C=O)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of 3-formyl-5-methyl-benzoic acid (3.80 g, 23.2 mmol), HOBt (4.17 g, 27.8 mmol) and EDC HCl (4.44 g, 23.2 mmol) in DMF (200 mL) was stirred at rt for 5 min before 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (4.50 g, 23.2 mmol) was added. The mixture was stirred at rt for 1 h. The mixture was heated to 75° C. and stirring was continued for 3 h. The mixture was concentrated to about 40 mL, acidified by adding formic acid (0.6 mL), diluted with a small amount of acetonitrile/water and separated by prep. HPLC (Waters XBridge Prep C18, 50×50 mm+50×100 mm, 10 μm, 80% to 10% water (containing 0.5% of formic acid) in MeCN) to give the title compound as a white solid (2.14 g). LC-MS**: tR=0.82 min; [M+1]+=323.15, 1H NMR (D6-DMSO): δ 1.20 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 2.55 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 7.71 (d, J=2.0 Hz, 2H), 8.05 (s, 1H), 8.32 (s, 1H), 8.49 (s, 1H), 8.95 (s, 1H), 10.14 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6].[CH3:24]I>O.CO>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:24])[S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6]
Reactant: CI
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of 8.2 gm (0.205 mol) of sodium hydroxide in 200 ml of water wasadded dropwise over a period of 40 minutes at a reaction temperature of 20°-25° C to a suspension of 61.0 gm (0.2 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 85.1 gm (0.6 mol) of methyl iodide in 500 ml of methanol. After stirring it for 4 hours, the mixture was cooled to +5° C, and the precipitate (= 50 gm of crude product) was suction-filtered off and washed with ice-cold methanol. The combined methanolic solutions were heated at 40° C for 15 minutes and then evaporated in vacuo until onset of crystallization. An additional 9 gm of crude product were obtained by suctionfiltration and washing with ice-coldmethanol. Recrystallization of the combined crude products from ethylene chloride yielded 53.3 gm (85% of theory) of 4 -hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide, m.p. 229°-230° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].ClC(Cl)(Cl)C([N:36]=C=O)=O>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:21]=2)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:36])[C:8]=2[N:18]=1)[CH3:2]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine (1.64 g, 3.90 mmol) in anhydrous dichloromethane (50 mL) was cooled to 6° C., and a solution of trichloroacetyl isocyanate (0.51 mL, 4.29 mmol) in dichloromethane (5 mL) was added dropwise. The solution was stirred for 30 minutes, and then the solvent was removed under reduced pressure. The residue was treated with sodium methoxide in methanol (10 mL of a 25% w/w solution) and methanol (40 mL). The resulting mixture was stirred for 18 hours at room temperature. A precipitate was present and was isolated by filtration, washed with methanol and diethyl ether, and dried under high vacuum at 80° C. for 18 hours to provide 0.999 g of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white solid, mp 190.0-191.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:15])[C:11](OC)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:16]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:15])[C:11]([NH2:16])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Product: CC(C(N)=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of methyl 2-(4-nitrophenyl)propionate (20.0 g) in aqueous ammonia (d=0.88, 350 ml) was stirred at room temperature for 36 h. The resultant solid was collected and dried in vacuo at 50° to give the title compound (13.4 g). A sample (0.1 g) was crystallised from water to give analytically pure material m.p. 120°-121°.