Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12](Br)[CH:13]=[CH2:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH:13]=[CH2:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)cc1
Reaction time: 16 h
Yield: 91 %

Procedure:
4-Allyloxybenzoic acid methyl ester was prepared by reacting 4-hydroxybenzoic acid methyl ester with allyl bromide following Method C in 91% yield. The reaction was conducted at room temperature for 16 h and the resulting product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)[N:8]=[CH:7]2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ncc2cccc(Br)c2n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 8-bromo-2-chloroquinazoline (7.3 g, 30 mmol) in acetonitrile (150 mL) was added trans-4-aminocyclohexanol (6.9 g, 60 mmol) to form a suspension. DBU (9.1 g, 60 mmol) was added. The reaction mixture was stirred at 45° C. overnight. A light yellow suspension was formed. The solvent was removed under reduced pressure, and the residue was taken into DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4 and purified by chromatography (eluting with DCM) to give the title compound as a light yellow solid (3.36 g, 35%). 1HNMR (DMSO-d6, 400 MHz): δ 9.10 (s, 1H), 8.02 (dd, J=1.2, 7.6 Hz, 1H), 7.81 (dd, J=1.2, 7.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.12 (dd, J=7.6, 7.6 Hz, 1H), 4.62-4.60 (m, 1H), 3.85-3.82 (m, 1H), 2.05-2.02 (m, 2H), 1.89-1.86 (m, 2H), 1.36-1.26 (m, 4H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:10]=[CH:9][C:8]2[O:11][CH2:12][CH2:13][O:14][C:7]=2[CH:6]=1)=[N+]=[N-]>[C].[Pd].C(O)C>[O:14]1[C:7]2[CH:6]=[C:5]([CH2:4][NH2:1])[N:10]=[CH:9][C:8]=2[O:11][CH2:12][CH2:13]1
Reactant: [N-]=[N+]=NCc1cc2c(cn1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: NCc1cc2c(cn1)OCCO2
Reaction time: 0.75 h

Procedure:
To 10 mL of an ethanol solution containing 0.53 g of 7-(azidomethyl)-2,3-dihydro-(1,4)dioxino(2,3-c)pyridine, 0.10 g of 5% palladium-carbon was added at room temperature, and the mixture was stirred for 1 hour and 45 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtain 0.46 g of a brown oily substance, 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methaneamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[N:14])=[CH:11][NH:10][CH:9]=1.[CH2:15]=[O:16]>C(N(CC)CC)C>[OH:16][CH2:15][N:10]1[CH:11]=[C:12]([C:13]#[N:14])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9]1
Reactant: N#Cc1c[nH]cc1-c1ccccc1Cl
Reactant: C=O
Solvent: CCN(CC)CC
Product: N#Cc1cn(CO)cc1-c1ccccc1Cl
Temperature: 90 °C

Procedure:
60.8 g of 3-(2-chlorophenyl)-4-cyanopyrrole, 9.9 g of paraformaldehyde and 0.8 g of triethylamine are thoroughly mixed and and the mixture is then heated, with stirring, at a bath temperature of 90° C. The resultant melt is cooled to room temperature after 11/4 hours, when it congeals to a glass-like solid. Recrystallisation from toluene yields the title compound in the form of brownish crystals of m.p. 94°-97° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:9]=[N:8][N:7]([CH3:10])[C:6]=1[C:11]([OH:13])=[O:12])=[O:4].CN1C=C(C(N2C[CH2:27][O:26][CH2:25]C2)=O)C=N1>>[CH3:10][N:7]1[C:6]([C:11]([OH:13])=[O:12])=[C:5]([C:3]([N:2]2[CH2:14][CH2:27][O:26][CH2:25][CH2:1]2)=[O:4])[CH:9]=[N:8]1
Reactant: Cn1cc(C(=O)N2CCOCC2)cn1
Reactant: CN(C)C(=O)c1cnn(C)c1C(=O)O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)O

Procedure:
This compound was prepared in analogy to 4-dimethylcarbamoyl-2-methyl-2H-pyrazole-3-carboxylic acid (Example 97, step b) from (1-methyl-1H-pyrazol-4-yl)-morpholin-4-yl-methanone (1.20 g, 6.15 mmol). Yield: 1.05 g (71%); off-white solid; MS: m/z=240.2 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].Cl[C:20](OCC)=[O:21]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]2[O:17][C:20](=[O:21])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(Br)ccc2oc(=O)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
Step 1 A solution of 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide (Intermediate 16-1, 40 mg, 0.131 mmol) in pyridine (1 mL) was treated with ethyl chloroformate (0.015 mL, 0.157 mmol) at rt and the mixture was heated to 100° C. for 2 h. Additional ethyl chloroformate (0.015 mL, 0.157 mmol) was added and the mixture was stirred at 100° C. for 15 h. The mixture was cooled and diluted with EtOAc (80 mL), and the solution was washed with NaHCO3 (aq) (10 mL), water (2×10 mL) and brine (10 mL), and dried and concentrated. The residue was purified by column chromatogaphy (eluting with a gradient from 95:5 to 70:30 hexane-EtOAc) to give 6-bromo-5-methyl-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (19 mg, 44%). 1H NMR (400 MHz, chloroform-d) δ 7.90 (1 H, d, J=9.02 Hz), 7.43-7.68 (3 H, m), 7.27-7.40 (2 H, m), 7.12 (1 H, d, J=8.80 Hz), 2.90 (3H, s). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:27][C:28](=[NH:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:37]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=3)[N:27]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
A solution of 4-isobutyl-benzoic acid (451 mg, 2.53 mmol) and 1,1′-carbonyldiimidazole (491 mg, 3.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. N-hydroxy-4-hydroxymethyl-benzamidine (420 mg, 2.53 mmol) was added to the reaction mixture, stirred at room temperature for 18 hours and diluted with ethyl acetate. The reaction mixture was washed with aqueous sodium hydroxide (0.25 N), water and brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was treated with a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.78 mL) and THF (6 mL) and stirred at room temperature for 12 hours. The reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by flash chromatography (silica, 1:9 to 2:3 EtOAc:hexanes) provided the title compound (193 mg, 29% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:33]([O-:35])=[O:34])=[C:15]([CH2:18][N+:19]4[N:20]([CH3:32])[C:21]([NH2:31])=[C:22]([N:24]([CH2:27][CH2:28][CH2:29][NH2:30])C=O)[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C(=O)([O-])O.[Na+]>CO>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:33]([O-:35])=[O:34])=[C:15]([CH2:18][N+:19]4[N:20]([CH3:32])[C:21]([NH2:31])=[C:22]([NH:24][CH2:27][CH2:28][CH2:29][NH2:30])[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Cn1c(N)c(N(C=O)CCCN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1c(N)c(NCCCN)c[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3nsc(N)n3)[C@H]2SC1
Reaction time: 6.5 h
Yield: 29.1 %

Procedure:
To a suspension of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[N-(3-aminopropyl)-N-formylamino]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate (140 mg) in methanol (2.6 ml) was added concentrated hydrochloric acid (0.176 ml) at room temperature, and the mixture was stirred for 6.5 hours. To the reaction mixture was added sodium hydrogen carbonate (177 mg), and the mixture was purified by preparative HPLC (ODS column, acetonitrile/phosphate buffer (pH 7)=5:95). The eluate containing a desired product was evaporated to remove acetonitrile, acidified with diluted hydrochloric acid and chromatographed on Diaion® HP-20 eluting with 20% aqueous 2-propanol. The eluate was concentrated under reduced pressure and lyophilized to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[(3-aminopropyl)amino]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate (39 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]12([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>CN(C)C=O>[Cl:1][C:30]1[CH:31]=[C:19]([C:9]23[CH2:10][CH:11]4[CH2:12][CH:13]([CH2:14][CH:15]([CH2:17]4)[CH2:16]2)[CH2:18]3)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Temperature: 0 °C

Procedure:
3.22 g of N-chlorosuccinimide are added to a solution of 7 g of 4-[4-(1-adamantyl)-phenoxy]-butyric acid in 40 ml of absolute dimethylformamide whilst stirring in an anhydrous atmosphere at 0° C. The mixture is then stirred for a further 15 minutes at 0° C, 30 minutes at about 25° C and 9 hours at 50° C. The reaction solution is cooled to 0° C, filtered and treated with 40 ml of ice water. The precipitate formed is filtered off and washed with ice water. It is then recrystallised twice from ethanol. 4-[2-Chloro-4-(1-adamantyl)-phenoxy]-butyric acid of melting point 164°-166° C is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:29](I)[CH2:30][CH3:31]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][N:15]([CH2:29][CH2:30][CH3:31])[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CCCI
Reactant: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CC=C(c2c[nH]c3cc(OC)ccc23)CC1
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A mixture of 10 g of the product of Step A, 200 ml of dimethylformamide, 9.28 g of sodium carbonate and 8.93 g of propyl iodide was stirred under an inert atmosphere for 5 hours and was then poured into 1.5 liters of water. The mixture was allowed to crystallize and was stirred for one hour and then vacuum filtered. The recovered product was rinsed with water and dried at 50° C. under reduced pressure in the presence of a dehydrating agent to obtain 9.9 g of 6-methoxy-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 219°-220° C.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[C:5]([NH:10][NH2:11])([CH2:8][CH3:9])([CH3:7])[CH3:6].Cl>O>[C:5]([NH:10][NH:11][C:2]([NH2:3])=[O:1])([CH2:8][CH3:9])([CH3:7])[CH3:6]
Reactant: N#C[O-]
Reactant: CCC(C)(C)NN
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCC(C)(C)NNC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13.6 g of potassium cyanate are added to a mixture of 17 g of tert-pentylhydrazine and 30 ml of water cooled in an ice bath and 16.5 g of conc. hydrochloric acid are then added dropwise. The mixture is stirred at room temperature for 3 h and the solid is filtered off with suction, washed with water and dried in vacuo.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=O>>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccn3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 76 mg (0.269 mmol) of 2-bromo-1-pyridin-2-ylethanone were reacted according to the General Method 3. Yield: 8 mg (7% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:15]3[C:16]([CH2:24][CH3:25])=[C:17]([C:19]([O:21]CC)=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:15]3[C:16]([CH2:24][CH3:25])=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc2c1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc3c(CC)c(C(=O)O)sc3c2)nc1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Ethyl 6-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethyl-1-benzothiophene-2-carboxylate obtained in Example (183f) (49 mg) was dissolved in methanol (2 ml) and THF (2 ml). A 2 N aqueous lithium hydroxide solution (2 ml) was added, and the mixture was stirred at 50° C. for 30 minutes. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water and ethyl acetate, and dried under reduced pressure at 45° C. to obtain 40 mg of the title compound as a solid.
Reaction SMILES: C(Cl)(Cl)=O.[NH2:5][C:6]1[CH:10]=[C:9]([Cl:11])[S:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=S)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[Cl:11][C:9]1[S:8][C:7]2[S:12](=[O:14])(=[O:13])[N:15]=[C:16]([NH:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[NH:5][C:6]=2[CH:10]=1
Reactant: CC(C)CCNC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 0 °C
Yield: 29.4 %

Procedure:
Phosgene (0.242 ml, 20% in toluene) was added dropwise to a solution of N-(3-amino-5-chloro-2-thienylsulfonyl)-N′-(3-methylbutyl)thiourea (0.153 g, 0.42 mmol) and dry triethylamine (0.118 ml, 0.85 mmol) in dry tetrahydrofuran (3 ml) with stirring at 0° C. The mixture was stirred for 2 h at 0° C., and evaporated to dryness. Crystallisation was obtained from ethyl acetate, and the precipitate was isolated by filtration, washed with water and dried affording 38 mg (27%) of the title compound. mp 230-231.5° C., 1H-NMR (DMSO-d6): δ0.90 (d, 6H, 2×CH3), 1.40 (q, 2H, CH2),1.60 (m, 1H, CH), 3.20 (q, 2H, CH2), 7.05 (s, 1H, H-5), 7.25 (br s, 1H, NH), 10.95 (s, 1H, NH). MS: M/e 307(M+).
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH2:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[C:7]([CH3:16])[C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:17]=O>S(=O)(=O)(O)O>[CH3:17][NH:6][C:5]1[C:7]([CH3:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([CH2:11][CH3:12])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCc1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]
Reactant: C=O
Agent: O=S(=O)(O)O
Product: CCc1c([N+](=O)[O-])cc(C)c(NC)c1[N+](=O)[O-]

Procedure:
This compound is made according to Scheme 1. 2,4-Dinitro-3-ethyl-6-methylaniline is treated with paraformaldehyde in concentrated sulfuric acid to afford N-methyl-2,4-dinitro-3-ethyl-6-methylaniline. The synthesis is completed in the same manner as 4-ethyl-5-(2-imidazolinylamino)benzimidazole (see Example 2).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]=[C:2]1[N:8]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cccc2c1NC(=O)CCC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1N(COCC[Si](C)(C)C)C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.500 g of methyl 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-9-carboxylate are dissolved under argon in 30 ml of N,N-dimethylformamide and the solution is cooled to 0° C. in an ice bath. 0.600 g of sodium hydride dispersion (60%) is added in portions and the reaction mixture is subsequently stirred at 0° C. over a further 1 hour. 0.502 ml of 2-(trimethylsilyl)ethoxymethyl chloride is added and the reaction mixture is subsequently stirred at room temperature over 11 hours. The reaction mixture is poured onto 150 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2×150 ml of tert-butyl methyl ether. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a reddish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (1:1 EtOAc-heptane); Rt=5.02.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.[I:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([I:17])=[N:8][C:6]=2[N:7]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
4-(5-Chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was dissolved in tetrahydrofuran and iodine (3 eq) was added. The solution was cooled to −50° C. and potassium bis(trimethylsilyl)amide (1.2 eq of 0.5M solution in toluene) was added over a period of 10 minutes. The solution was warmed to room temperature and stirred overnight. Water was added to quench the reaction and the tetrahydrofuran was removed in vacuo. The residue was brought up in methylene chloride, washed with saturated sodium bicarbonate solution and dried with magnesium sulfate. The solution was concentrated a purified by silica gel chromatography to yield 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2].CCOC(C)=O>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(O)cc1
Reaction time: 4 h
Yield: 98.2 %

Procedure:
Ethyl-4-benzyloxyphenoxyacetate compound (3.50 g, 12.2 mmol) was placed in a PARR bottle along with EtOAc (75 mL), EtOH (75 mL), and 5% Pd/C (1.20 g) and the mixture placed under 40 psi of H2. The reaction was shaken under pressure for 4 hours after which no starting material remained by TLC. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to give 2.35 g (97%) of the desired phenol. MP
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl quinoxaline-6-carboxylate (500 mg, 2.66 mmol) in 10 mL of THF was added sodium hydroxide (5N, 2.5 mL, 12.5 mmol) followed by methanol (2.5 mL). The reaction was stirred at room temperature overnight and then concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with 1N HCl until the pH was slightly acidic (pH=5). The resulting solution was extracted with EtOAc (3×), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification. LC-MS: 3.50 min. (M+H)=175.16.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[N:13][N:12]2[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:11]2[C:10]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:36]=1)[C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH3:2].[H][H]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[N:13][N:12]2[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:11]2[C:10]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:36]=1)[C:26]([OH:28])=[O:27])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C(=O)O)c1
Yield: 100.6 %

Procedure:
A mixture of benzyl 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinate (330 mg) and 10% palladium on carbon (33 mg) in methanol (10 mL) was stirred under 4 atm hydrogen atmosphere at ambient temperature for 2 hours. The catalysts were filterred off and washed with chloroform. The filtrates were evaporated in vacuo to give 5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinic acid as yellow oil (272 mg)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1.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>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2
Reactant: COc1ccc(Br)c2c1CCC(=O)N2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2
Yield: 83.9 %

Procedure:
8-Bromo-5-methoxy-3,4-dihydro-1H-quinolin-2-one (10.0 g), tetrakis(triphenylphosphine)palladium (0.45 g) and potassium carbonate (5.4 g) were suspended in dioxane (100 ml), and phenylboronic acid (5.24 g) was added, followed by heating under reflux in an argon atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was subjected to extraction with ethyl acetate. The extract was washed twice with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 8.3 g (yield: 84%) of 5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one as a light yellow powder.