Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: OCc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(CO)cc1
Reaction time: 18 h
Yield: 35.9 %

Procedure:
A mixture of 4-hydroxybenzylalcohol (1.52 g, 12.2 mmol.), allyl bromide (1.1 ml, 12.2 mmol.), acetonitrile (40 ml), and potassium carbonate (2.54 g, 18.4 mmol.) was reluxed for 18 hours, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to give the product as a yellow oil (0.72 g, 71%). 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 1H), 4.55 (m, 2H), 4.6 (s, 2H), 5.3 (d, 1H, J=11.5 Hz), 5.43 (d, 1H, J=16.5 Hz), 6.1 (m, 1H), 6.94 (m, 2H), 7.33 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 65.3, 69.2, 115.2, 118.1, 129.0, 129.4, 133.7, 158.6.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][N:2]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: ClCCN1CCOCC1
Reactant: CNc1nc2ccc([N+](=O)[O-])cc2s1
Agent: Cl
Product: CN(CCN1CCOCC1)c1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
The title compound is prepared according to the general procedure outlined in Example 61, Step 2, utilizing methyl-(6-nitro-benzothiazol-2-yl)-amine (1.18 g, 5.64 mmol) and N-(2-chloroethyl)-morpholine hydrochloride (2.45 g, 13.17 mmol) to yield 1.43 g (79%) of the product. mass spectrum (ion-spray): (m/z)=323.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:27])([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:21]#[N:22]>>[C:21]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:27])[CH2:23][CH:24]1[CH2:26][CH2:25]1)#[N:22]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(N)(C#N)CC1CC1
Product: CC(C#N)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Amino-3-cyclopropyl-2-methyl-propionitrile (example 66a) as starting materials and isolated (376 mg, 67%); MS (ESI, m/z): 368.6 (M+H+).
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[O:17][CH2:18][CH:19]2[O:21][CH2:20]2)=[N:9]1)C1C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[NH:30][CH2:31][CH2:32][NH2:33]>C(Cl)Cl>[NH:9]1[C:10]2[C:15](=[C:14]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:33][CH2:32][CH2:31][NH:30][C:24]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:22])[CH:13]=[CH:12][CH:11]=2)[CH:16]=[N:8]1
Reactant: c1ccc(Cn2cc3c(OCC4CO4)cccc3n2)cc1
Reactant: Cc1cccc(C)c1NCCN
Solvent: ClCCl
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2[nH]ncc12

Procedure:
6.2 g. 2-Benzyl-4-(2,3-epoxypropoxy)-indazole and 7.2 g. 2-(2,6-dimethylphenylamino)-ethylamine are stirred for 20 hours at 70° C. The reaction mixture is then dissolved in methylene chloride and purified chromatographically over a silica gel column using methylene chloride/methanol (saturated with ammonia) (20:1 v/v) as elution agent. After evaporation, the desired compound is obtained in the form of a viscous oil in a yield of 6.8 g. (69% of theory).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH:17]([CH3:18])[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[ClH:28].[CH3:29][CH:30]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:31](=[O:32])[CH:30]([CH3:29])[CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:7]2[C:8]3[CH:17]([CH3:18])[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CCS1
Reactant: CC(CCN1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CCS1

Procedure:
1,2-dihydro-10-hydroxy-8-(3-methyl-2-octyl)-1,5,5-trimethyl-3H,5H-thiopyrano[2,3-c][1]benzopyran is reacted with 2-methyl-4-piperidinobutyric acid hydrochloride in methylene chloride in the presence of dicyclohexylcarbodiimide, according to the procedure of Example 28, to produce the desired ester.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[CH:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[CH:10][C:11]([OH:13])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCC1CCCCC1=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC1CCCCC1=CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 2-(2-allylcyclohexylidene)acetate (1.00 g, 4.230 mmol) in dichloromethane (40 mL) at room temperature was added trifluoroacetic acid (0.688 mL, 8.883 mmol) and the solution was stirred at room temperature overnight. The solvent was then evaporated and excess of trifluoroacetic acid was removed by co-evaporation with toluene, giving 2-(2-allylcyclohexylidene)acetic acid (768 mg, 100%) as a colorless oil; 1H NMR (400 MHz, CDCl3) 5.59 (1H, m), 5.46 (1H, s), 4.82 (2H, m), 3.36 (1H, m), 2.19 (1H, m), 2.12 (2H, m), 1.93 (1H, m), 1.71 (1H, m), 1.61 (1H, m), 1.55 (1H, m), 1.47 (2H, m), 1.22 (1H, m).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:34](#[N:37])[CH:35]=C>>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:35][C:34]#[N:37])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C=CC#N
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Product: CCCCc1nnc(OC2CCN(CCC#N)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine (Example 14, 0.244 mmol, 100 mg) and acrylonitrile (1 mL) may be stirred at room temperature for 20 h. The organic solvent may be removed in vacuo, and the residue may be purified by column chromatography on silica gel using 1-2% of MeOH in DCM to provide 3-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-propionitrile.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)[C:45](N)(CO)[CH2:46][OH:47].[O:52]1CCC[CH2:53]1>O>[N:30]([CH2:27][CH2:26][OH:41])([CH2:31][CH2:53][OH:52])[CH2:45][CH2:46][OH:47].[C:1]([NH:9][C@@H:10]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:43])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[C:26]([O:41][CH3:42])[CH:25]=2)=[CH:19][CH:20]=1)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(CO)(CO)CO
Reactant: C1CCOC1
Agent: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)O)NC(=O)c3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: O
Product: OCCN(CCO)CCO
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A mixture of (R)-3-benzoylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetyl-amino}phenyl)-propanoic acid [1.0 g, Example 5(a)], tris(hydroxymethyl)aminomethane (0.208 g), tetrahydrofuran (80 ml) and water (15 ml) was stirred at 50° C. for 1.5 hours, then cooled to room temperature and then evaporated. The residue was recrystallised from ethanol to give the title compound as a white crystalline solid (1.1 g), m.p 135-140° C. (with decomposition). [Elemental analysis:—C, 61.6; H, 6.1; N, 9.5%. Calculated for C33H32N4O6.C4H11NO3.H2O:—C, 61.75; H, 6.3; N, 9.7%].
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH:29]([CH3:31])[CH3:30]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CC(C)Br
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OC(C)C)c2)n1

Procedure:
Using the compound obtained in Example 97 and 2-bromopropane, white solid N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:9]=[C:8]([CH3:25])[C:4]=1[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C([Cl:29])=O>COCCOC.CN(C)C=O>[CH2:1]([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:9]=[C:8]([CH3:25])[C:4]=1[C:5]([Cl:29])=[O:6])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CCc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Cl
Temperature: 40 °C

Procedure:
Under an argon atmosphere, the compound prepared in Example 18 (79 g) was dissolved in 1,2-dimethoxyethane (500 mL). The reaction mixture was added with anhydrous N,N-dimethylformamide (3 drops) and oxalyl chloride (24 mL), and stirred at 40° C. for an hour. The reaction mixture was concentrated to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.CN1CCCC1.Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20].CCOC(C)=O>C1COCC1.C(Cl)Cl.O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])[CH:6]=[N:7][CH:8]=1
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: C=C(C)OC(=O)Cl
Agent: CN1CCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(C)OC(=O)Nc1cncc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-(trifluoromethyl)pyridin-3-amine (883 mg, 5.45 mmol) was suspended in dry THF (20 mL) and N-methylpyrrolidine (680 μL, 6.54 mmol) was added to give a brown suspension. The mixture was cooled to 0° C. and isopropenyl chloroformate (715 μL, 6.54 mmol) was added dropwise over 15 min. The suspension was allowed to reach RT and was stirred for 4 h. EtOAc (60 mL) and H2O (10 mL) were added and the organic layer was isolated, washed with 50% brine (10 mL), dried (MgSO4), filtered and evaporated to leave a brown oil, which solidified upon standing (1.05 g). The solid was taken up in CH2Cl2 (4 mL) and purified by column chromatography on silica gel, eluting with EtOAc in CH2Cl2 (6%→40%), to give a white solid. Yield: 600 mg (45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=1.N[CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:33]([O:32][C:30]([N:28]1[CH2:29][CH:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=2)[CH2:27]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC1C(=O)NN=C2COc3cc(Oc4ccccc4)c(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Oc4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 11.3 %

Procedure:
A mixture of 6-amino-4-methyl-7-phenoxy-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.090 g, crude from previous step), tert-butyl 3-aminoazetidine-1-carboxylate (0.087 g, 0.51 mmol) and sodium cyanoborohydride (0.00032 g, 0.51 mmol) in MeOH (2.7 mL) and AcOH (0.3 mL) was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and diluted with MeOH (10 mL). The solution was purified by preparative HPLC (Table 3, Method 3) to give 3-(4-methyl-3-oxo-7-phenoxy-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.015 g, 12% over 2 steps) as a colorless oil. LC/MS (Table 1, Method 2) Rt=1.188 min; MS m/z: 502 [M+23]+
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]([CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=O>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:25][CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1
Reactant: BrC(Br)(Br)Br
Reactant: O=CC1CCC(=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCC(C=C(Br)Br)CC1
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
A solution of 36.72 g of triphenylphosphine in 200 ml of methylene chloride was treated slowly at -20° C. with 23.22 g of carbon tetrabromide and stirred for a further 10 minutes. Subsequently, the mixture was added dropwise by means of a cannula to a solution, cooled to -60° C., of 6.30 g of 4-formylcyclohexanone in 100 ml of methylene chloride. The mixture was stirred at -60° C. for a further 15 minutes and then partitioned in water/methylene chloride. The aqueous phases were extracted a further twice with methylene chloride. The organic phases were washed twice with water, dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting, pale yellow oil (16 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 12.08 g (85.8%) of 4-(2,2-dibromovinyl)cyclohexanone as a pale yellow liquid.
Reaction SMILES: C(=O)(O)[O-].[Na+].CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[Na].[NH2:25][N:26]1[C:30]([SH:31])=[N:29][N:28]=[N:27]1.CS(O)(=O)=O>O>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:31][C:30]3[N:26]([NH2:25])[N:27]=[N:28][N:29]=3)[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nn1nnnc1S
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a solution of sodium bicarbonate (9.24 g, 0.11 mol) in water (1 liter) was added 7β-aminocephalosporanic acid (27.2 g, 0.1 mol) and the mixture was stirred until solution results. The sodium salt of 1-amino-5-mercapto-1H-tetrazole (27.8 g, 0.2 mol) was added to the mixture and allowed to react in an argon stream between 52° C. and 53° C. for 3 hours. An additional amount of the sodium salt of 1-amino-5-mercapto-1H-tetrazole (6.95 g, 0.5 mol) was added to the mixture and allowed to react at the same temperature for 2 hours. The mixture was then passed three times through a layer of activated carbon (15 g) in order to decolorize it. The filtrate was adjusted to pH 4.6 with methanesulfonic acid (about 6 ml) under ice-cooling and set aside to precipitate. The precipitated substance was filtered, washed with water and dried in vacuo over phosphorus pentoxide to give ocherous powder of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (17.3 g, 52%), mp~206° C. (decomposition).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH:6]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19]C(=O)C(C)(C)C)[N:16]=[C:15]([NH:26]C(=O)C(C)(C)C)[CH:14]=1)C.O.[Li+].[OH-]>C1COCC1>[NH2:19][C:17]1[N:16]=[C:15]([NH2:26])[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:33]2[CH:34]=[N:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:5][C:4]([OH:43])=[O:3])[N:18]=1
Reactant: CCOC(=O)CC(CCCCCCc1cc(NC(=O)C(C)(C)C)nc(NC(=O)C(C)(C)C)n1)c1cnc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(CCCCCCC(CC(=O)O)c2cnc3ccccc3c2)nc(N)n1

Procedure:
The ester 7-8 (1 g, 1.7 mmol) was dissolved in THF (20 mL) and water (20 mL) and treated with 1N LiOH (7 mL) at room temperature for 16 hours. After neutralization with 3N HCl, the solution was concentrated in vacuo, filtered through a bed of silica gel (EtOH:H2O:NH4OH 10:1:1) and the residue purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 7-9 (TFA salt) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:7](=O)[NH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1.P(Cl)(Cl)([Cl:16])=O>C(#N)C>[Cl:16][C:7]1[N:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc2c(=O)[nH]ccc2c1
Solvent: CC#N
Product: COc1cnc2c(Cl)nccc2c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
To a mixture of 3-methoxy-1,7-naphthyridin-8(7H)-one (4.50 g, 25.5 mmol) in acetonitrile (102 ml) was added phosphorus oxychloride (11.69 ml, 128 mmol). The reaction mixture was heated to 85° C. for 5 h. The solution was cooled to rt and concentrated in vacuo. The resulting brown residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, the filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (5%-30% of 9:1 DCM:MeOH in DCM) to afford 8-chloro-3-methoxy-1,7-naphthyridine (3.00 g, 15.41 mmol, 60.3% yield) as an off-white solid. MS m/z=195 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[CH:7][C:8]=2[CH3:15])[N:3]=1.[NH2:17][NH2:18]>>[NH:17]([C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[C:5]([CH3:16])[CH:6]=[CH:7][C:8]=2[CH3:15])[N:3]=1)[NH2:18]
Reactant: Cc1ccc(C)c2c(C(C)C)cc(Cl)nc12
Reactant: NN
Product: Cc1ccc(C)c2c(C(C)C)cc(NN)nc12

Procedure:
A solution of 2-chloro-4-isopropyl-5,8-dimethylquinoline (1.00 g, 4.3 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.30 (d, J=6.74 Hz, 6 H) 2.64 (s, 3 H) 2.82 (s, 3 H) 3.95-4.10 (m, 1 H) 6.72 (s, 1 H) 6.98 (d, J=7.33 Hz, 1 H) 7.30 (d, J=7.33 Hz, 1 H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+:21].[Cs+]>O>[C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Cs+:21]
Reactant: O=C(O)CCCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=C([O-])CCCC(=O)OCc1ccccc1

Procedure:
Crude benzyl hydrogen glutarate (25 g, 100 mmol) is stirred in water (100 ml) to form a slurry. An aqueous solution of 1M cesium carbonate is added until the pH reaches 7 (52 ml is consumed). The homogeneous reaction mixture is diluted with water (150 ml), and extracted with chloroform (2×50 ml) to remove nonpolar impurities from the crude starting material. Water is removed in vacuo, and the oily, grayish semicrystalline residue is slurried in dimethylformamide (200 ml), and evaporated to dryness in vacuo. This procedure is repeated twice, yielding an off-white crystalline product, which is used without further characterization.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[ClH:12]>CN(C)C=O.[Cu](Cl)Cl>[Cl:12][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: Cl
Agent: Cl[Cu]Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
Copper(II)chloride (10.01 g, 74.5 mmol) was dissolved in N,N-dimethylformamide (75 mL) and the solution was warmed to 60° C. A solution of 2-amino-4-methyl-5-nitropyridine (9.50 g, 62.0 mmol) in N,N-dimethylformamide (145 mL) was added with addition funnel over 0.5 h. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature and poured into 3 N aqueous hydrochloric acid (300 mL), followed by extraction with diethyl ether. The organic extract was dried over sodium sulfate and adsorbed onto silica gel for purification by column chromatography (SiO2, 20:3 hexanes/ethyl acetate). 2-Chloro-4-methyl-5-nitropyridine was obtained as a yellow solid (2.10 g, 20%): 1H NMR (300 MHz, CD3OD) δ2.63 (3H, s), 7.60 (1H, s), 8.96 (1H, s); ESI MS m/z 173 [C6H5ClN2O2+H]+.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([CH3:9])[CH2:6][N:5]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28]C)=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[OH-].[Na+]>O1CCOCC1.O>[CH3:2][CH:3]1[CH2:8][CH:7]([CH3:9])[CH2:6][N:5]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[N:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([OH:28])=[O:27])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:4]1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CC(C)CC(C)C4)n3)c3nccn3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CC(C)CN(c2cccc(Nc3cc(-c4cccc(C(=O)O)c4)nn4ccnc34)n2)C1
Yield: 69.8 %

Procedure:
To a stirred solution of methyl 3-(8-(6-(3,5-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate hydrochloride (0.025 g, 0.055 mmol) in dioxane (10 mL) and H2O (5 mL) was added NaOH (22 mg, 0.55 mmol) at 40° C. After 2 h the mixture was washed with ether (10 mL) and the aqueous layer was adjusted to pH=4, then filtered. The solid was washed with ether and dried to afford 3-(8-(6-(3,5-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.017 g, 70%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.99 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.19 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.84 (s, 1H), 7.71-7.49 (m, 2H), 6.76-6.72 (m, 1H), 6.52-6.48 (m, 1H), 4.22 (d, 1H, J=12.6 Hz), 3.65-3.59 (m, 1H), 3.28-3.21 (m, 1H), 2.33 (t, 1H, J=12.0 Hz), 1.92-1.41 (m, 4 h), 0.80-0.69 (m, 6H). LC-MS: [M+H]+, 443, tR=1.825 min, HPLC: 98.43% at 214 nm, 99.05% at 254 nm, tR=6.85 min.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1.[CH2:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:28]([CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCCCC
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Yield: 85.2 %

Procedure:
0.66 g (2 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 75° overnight with 1.2 g (9.3 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.72 g (85%) of 3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 211°-213°.