Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1[N:22]([CH2:26][CH2:27][O:28][CH3:29])[C:23](=[O:25])[CH3:24].C(OCC)(=O)C>C1C=CC=CC=1>[CH2:1]([NH:8][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1[N:22]([CH2:26][CH2:27][O:28][CH3:29])[C:23](=[O:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COCCN(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COCCN(C(C)=O)C1=C(NCc2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzylamine (0.5 ml) was added to a solution of N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (0.5 g) in benzene (15 ml) and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate-hexane to give N-(3-benzylamino-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (0.51 g) as a red powder.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17]O)[CH:5]=1.CS(Cl)(=O)=O.[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH:32]1[CH2:37][N:38]([CH3:40])[CH3:39])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([CH2:17][CH2:16][CH2:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([N:4]4[CH:3]=[N:2][N:1]=[CH:5]4)[CH:7]=3)[NH:11][CH:10]=2)[CH2:33][CH:32]1[CH2:37][N:38]([CH3:40])[CH3:39])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)CC1CNCCN1Cc1ccccc1
Reactant: OCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC1CN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propan-1-ol (0.490 g, 2.02 mmol) in THF (100 mL) was added triethylamine (0.62 ml), 6.0 mmol) followed by methanesulphonyl chloride (0.35 mL, 3.03 mmol) and the mixture stirred at 25° C. for 1.5 h. The reaction mixture was filtered and the solvent evaporated. The residue was dissolved in DMF (50 mL) and potassium carbonate (0.35 g) added followed by a solution of 1-benzyl-2-(N,N-dimethylaminomethyl)piperazine (step 2) (0.52 g, 2.22 mmol) in DMF (20 mL). The reaction was heated at 85° C. under N2 for 4 days. The solvent was then removed in vacuo and the residue taken up in ethyl acetate (50 mL) and washed with H2O (3×20 mL). The organic layer was dried (MgSO4) and evaporated. The residue was chromatographed on silica eluting with CH2Cl2 →6% MeOH-1% NH3 --CH2Cl2 to obtain a pale yellow oil that was treated with a solution of oxalic acid in ethyl acetate to obtain a white solid that was filtered and dried to obtain 4-benzyl-3-(N,N-dimethylaminomethyl)-1-[3-(5-(1,2,4-triazol-4-yl) -1H-indol-3-yl)propyl]piperazine oxalate, 105 mg. 1H nmr (free base, 250 MHz, CDCl3) δ 1.92 (2H, m), 2.05-2.9 (13H, m), 2.21 (6H, s), 3.22 (1H, d), 4.20 (1H, d), 7.12 (2H, m), 7.23-7.31 (5H, m), 7.46 (1H, d, J=4 Hz), 7.55 (1H, d, J=1 Hz), 8.38 (1H, br s), 8.46 (2H, s). MS (m/z) 458 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][C@H:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1
Reactant: CN1CCC[C@H](c2nnc3ccc(F)cn23)C1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC[C@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate A (196 mg, 1.20 mmol) in dry DMF (3 mL) at RT under N2 was added NaH (60% dispersion in oil, 80 mg, 2.00 mmol) and the resulting opaque brown solution stirred for 45 min. A solution of Intermediate 88d (234 mg, 1.00 mmol) in dry DMF (2 mL) was added and the resulting dark brown solution stirred at 60° C. for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.1 mL), applied to and SCX-2 cartridge and washed with MeOH (75 mL). The product was eluted with 2M NH3 in MeOH (60 mL); concentration in vacuo left a dark brown solid. FCC, using 3-13% [2M NH3 in MeOH] in DCM, gave the title compound as a light brown solid after freeze-drying (280 mg, 74%). LCMS (Method 3): Rt 0.44 min, m/z 378 [MH+].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[Br-:19].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.C(=O)([O-])O.[Na+]>C(O)(C)C>[Br:19][CH2:17][C:16]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:15])[F:14])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1)=[O:18]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(CBr)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 116.4 %

Procedure:
To 250 ml of isopropanol solution containing 10.8 g (42.3 mmol) of 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanone (see WO 9206963) was added 36.5 g (97.1 mmol) of trimethylphenylammonium tribromide at room temperature, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure to obtain 16.5 g of the title compound as a pale yellowish solid substantially quantitatively.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[Cl:39])[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:39][C:16]1[CH:17]=[CH:18][C:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(Cl)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of product from Step E (2.10 g, 3.74 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (4 mL). The resulting solution was stirred for 2 hours, then poured onto saturated aqueous sodium bicarbonate, and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title product without further purification.
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24]C(C)(C)[O:26][C:27](=O)[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3([C:19]#[N:20])[CH2:18][CH2:17]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]4([C:19]#[N:20])[CH2:18][CH2:17]4)=[C:11]([F:21])[CH:10]=3)[CH2:22][C:23](=[O:24])[CH2:28][C:27](=[O:26])[O:32]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2cc(F)c(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: N#CC1(c2c(F)cc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1

Procedure:
The desired product was prepared analogously to step of example A (97), substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2,6-difluorophenyl}-cyclopropanecarbonitrile (1.0 g, 2.66 mmol) from Step 2 below in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. Yield: 0.43 g, 42%. δ: 1H NMR (CDCl3) δ: 1.35 (t, J=2.8 Hz, 2H), 1.56-1.73 (m, 10H), 1.92 (t, J=4.45 Hz, 2H), 2.21-2.30 (m, 1H), 2.65-2.79 (m, 4H), 3.44 (d, J=5.6 Hz, 2H), 6.71(d, J=8.6 Hz, 2H). MS (ESI): 386 (M−1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:14]([CH3:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:14]([CH3:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: FCBr
Reactant: COC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(=NOCF)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
14.2 g of potassium carbonate was added to a solution of 14.5 g of methyl 2-hydroxyimino-acetoacetate in 50 ml of dimethylsulfoxide, and then 11.6 g of fluoro-bromomethane in 9 ml of N,N-dimethylformamide was added dropwise thereto. The mixture was stirred for 1 hour 30 minutes at room temperature, then poured into ice-water, and the resultant mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over Na2SO4 and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (120 g) with a mixture solvent of ethyl acetate and toluene (1/4 volume) as a eluent to give 4.7 g (27% yield) of methyl 2-fluoromethoxyiminoaceto-acetate (syn isomer).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C(=O)C.CN(C)CCN(C1C=CC(Cl)=CN=1)C(=O)C>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)N(CCN(C)C)c1cccnc1
Agent: CC(=O)N(CCN(C)C)c1ccc(Cl)cn1
Product: CN(C)CCNc1cccnc1

Procedure:
The title compound is prepared by following the procedure of Example 15, Part B, except substituting N-(2-dimethylaminoethyl)-N-(3-pyridyl)acetamide from Part A above for N-(2-dimethylaminoethyl)-N-(5-chloro-2-pyridyl)acetamide. The product has b.p. 87°-90°/0.4 mm.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[C:27](Cl)(=[O:29])[CH3:28].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[S:3][C:4]=3[N:5]=2)[CH:13]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl)carbamate (1.20 g, 3.22 mmol) in pyridine (20 mL) was added acetyl chloride (575 μL, 8.06 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), filtered through a basic silica gel pad, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (1.31 g, 98%) as a pale-purple solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Br[C:23]1[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:23]3[S:24][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)[CH2:14][C@H:13]2[NH:18][CH2:19][CH2:20][CH3:21])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCN[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 65.2 %

Procedure:
The same operation as in Example (196c) was performed using cis(±)-4-chloro-5-ethyl-N-[3-(propylamino)piperidin-4-yl]-1H-imidazole-2-carboxamide obtained in Example (205a) (17.0 mg, 0.054 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (15 mg, 0.060 mmol) and sodium carbonate (17 mg, 0.163 mmol), to obtain 17 mg of the title compound (65%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution 2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenol (900 mg, 2.5 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (1.62 g, 4.9 mmol, 2 eq). The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (540 mg, 2.9 mmol, 1.2 eq) was added dropwise. The reaction was stirred at room temperature for 30 min, then water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc 20:1 to 5:1) to give the title compound (300 mg, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=3)[NH2:17])[N:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([NH:17][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])[CH:18]=3)[N:11]=2)[N:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)cn2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
To a stirred solution of 5-(6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.050 g, 0.206 mmol) in acetonitrile (5 mL) containing pyridine (0.618 mmol) is added trimethylacetylchloride (0.206 mmol). The mixture is stirred at room temperature for 4 hours, concentrated to dryness, then purified via chromatography (hexanes to EtOAc) to afford the title compound (0.060 g, 86%) as a white solid: Rf 0.57 (EtOAc); LCMS (m/z)=339.4 [M+H]+, tR=6.37 min. (10 min run)
Reaction SMILES: CO.C(O[C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[CH2:26]([CH2:28][NH2:29])[OH:27]>O>[OH:27][CH2:26][CH2:28][NH:29][C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7]
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Reactant: NCCO
Solvent: O
Solvent: CO
Product: CSc1ncc(C(=O)NCCO)c(Nc2ccc3[nH]ncc3c2)n1
Yield: 72 %

Procedure:
To the solution of methanol (20 ml) was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1 g) prepared from preparation example 1, added ethanol amine (7 ml) at room temperature, and refluxed for 4 hr. The reaction mixture was cooled and slowly added H2O (40 ml) at 20° C. and stirred for 0.5 hr. The reaction mixture was filtered, washed with 25% aqueous methanol solution (10 ml), obtained the desired compound (0.75 g, 72%)
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[CH:5]=[CH:4][C:3]1=2.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid (Compound E19, 150.0 mg, 0.484 mmol), ethyl 4-hydroxybenzoate (88.5 mg, 0.530 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120.6 mg, 0.630 mmol), and 4-N,N-dimethylaminopyridine (77.0 mg, 0.630 mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc (50 mL) was added and the solution washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure and column chromatography (10-15% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].O1CC[CH2:39][CH2:38]1.C([Mg]Br)C.Cl>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]([OH:18])[CH2:38][CH3:39])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -73 °C
Yield: 30.6 %

Procedure:
To a cooled (-73° C.), stirred solution of 1.559 g. of benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate and 20 ml. of dry tetrahydrofuran was added 3.13 ml. of 2.88 M. ethyl magnesium bromide. After the reaction mixture was allowed to stir for four minutes at -73° C., 10 ml. of 1N.HCl was added and the solution allowed to warm to 0° C. The reaction mixture was transferred to a separatory funnel with the aid of cold ethyl acetate and cold 1N.HCl. The organic layer was separated and washed twice with cold 1N.HCl and twice with brine and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided a product residue which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.140 g. of the starting 3-formyl-2-cephem ester and 0.507 g. (30.6 percent) of the title product as a mixture of diasteromers:
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[N:4]=1.[C-:41]#[N:42].[K+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:21]=1)[N:4]=[C:3]2[CH2:2][C:41]#[N:42]
Reactant: [C-]#N
Reactant: COc1cc2c(CCl)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(CC#N)nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
3-Chloromethyl-5,6-dimethoxy-1(1-trityl-4-imidazolyl)methyl-1H-indazole (165.0 g) was suspended in dimethyl sulfoxide (1200 ml) and the solution was stirred at room temperature. Then potassium cyanide (43.6 g), which had been ground in a mortar, was added thereto. After stirring at 70° C. for 1 hour, the reaction mixture became homogeneous and transparent. The reaction mixture was returned to room temperature and poured into water (15000 ml) while vigorously stirring. The stirring was continued for 1 hour. The solid thus precipitated was collected by filtration, washed with water (1000 ml×3), dissolved in chloroform (5000 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using a silica gel column (ethyl acetate) to give 108.7 g of a pale brown solid. This solid product was used in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)[C:50]1=[O:62]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)[C:50]1=[O:62])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCN(c2cccnc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4cccnc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-(pyridin-3-yl)azepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (34 mg, 0.061 mmol) and Intermediate 67 (24 mg, 0.055 mmol) to give a white solid (17 mg, 35% yield). Anal. Calcd. for C42H51N5O6S m/z 753.7. found: 754.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 10.68 (s, 1H), 8.90 (d, J=1.9 Hz, 1H), 8.68 (d, J=5.4 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.82 (dd, J=8.4, 5.5 Hz, 1H), 7.28-7.08 (m, 9H), 7.02 (d, J=6.9 Hz, 1H), 5.31 (t, J=4.5 Hz, 1H), 5.21-5.04 (m, 1H), 5.03-4.93 (m, 1H), 4.92-4.79 (m, 1H), 4.08 (dd, J=15.6, 11.6 Hz, 1H), 3.83-3.71 (m, 1H), 3.68 (s, 3H), 3.22-3.04 (m, 1H), 2.91-2.68 (m, 5H), 2.55-2.33 (m, 3H), 2.16-1.90 (m, 4H), 1.91-1.43 (m, 13H), 1.41-1.21 (m, 1H).