Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1Cl

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (390 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH2:23][CH2:24][CH3:25])/[C:18]([O:20]CC)=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CCOC(C)=O>[Br:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH2:23][CH2:24][CH3:25])/[C:18]([OH:20])=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCC/C(=C\c1c(Br)c(OC)c2ccccc2c1OC)C(=O)OCC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Product: CCC/C(=C\c1c(Br)c(OC)c2ccccc2c1OC)C(=O)O

Procedure:
Compound 99f was prepared from 98f (0.177 g, 0.435 mmol) as described above for 29a to give 0.078 g (0.21 mmol, 47%) of the product as a white solid following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.[CH3:21][O:22][C:23](=[O:29])[CH:24]([CH:26]([CH3:28])[CH3:27])[NH2:25].C(OCC)C>C(Cl)Cl>[O:13]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:25][CH:24]([CH:26]([CH3:28])[CH3:27])[C:23]([O:22][CH3:21])=[O:29]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)C(N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)C(NCC(=O)c1ccccc1)C(C)C

Procedure:
Diisopropylethylamine (7.66 ml) and 2-bromoacetophenone (4.2 g) are added to a suspension of DL-valine methyl ester hydrochloride (3.36 g, Reference compound No. 45-1) in methylene chloride (100 ml), and the mixture is refluxed for four days. The reaction mixture is allowed to stand at room temperature, diethyl ether is added to the mixture, and the whole is extracted with 0.1 N hydrochloric acid. Sodium hydrogencarbonate is added to the extract to basify the system, and the whole is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure to give the titled reference compound (4.92 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CNCc2cccc(Br)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromopicoline aldehyde (0.520 g) and 2,4-dimethoxybenzylamine (0.504 mL) were dissolved in tetrahydrofuran (25 mL), acetic acid (0.176 mL) was added thereto, and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (889 mg) was added thereto, and the mixture was stirred in a second straight night at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (930 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[CH:12]=[C:11]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[N:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[CH:12]=[C:11]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[N:10]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([NH:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35]
Reactant: Cc1cc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)ccc1N
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)ccc1NC(=O)Nc1ccccc1
Temperature: 75 °C
Yield: 24.9 %

Procedure:
2-Methyl-4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]aniline (130 mg, 0.34 mmol) was dissolved in 1,4-dioxane (4 mL). Phenylisocyanate (0.038 mL, 0.34 mmol) was added and the reaction heated at 75° C. for 3 hours. The reaction mixture was evaporated to dryness and the resultant residue triturated with ethyl acetate to give the desired compound as a cream solid (42 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[Cl:1]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]nc(Cl)c2c1

Procedure:
1.00 g (5.06 mmol) of 3-chloro-5-nitro-1H-indazole was suspended in 50 ml of ethanol, and 5.71 g (25.3 mmol) of tin(II) chloride dihydrate were added. The mixture was left to stir at reflux overnight, saturated aqueous sodium bicarbonate solution was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed under reduced pressure. The mixture was triturated with tert-butyl methyl ether and the solid was filtered off with suction. Yield: 544 mg (purity 90%, 58% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[C:21]3[CH:20]=[C:19]([N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][C:12]([N:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>ClCCl>[CH:15]([C:16]1[CH:17]=[CH:18][C:19]([CH2:1][O:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3([C:48]4[CH:49]=[CH:50][C:51]([O:54][CH2:55][C:3]5[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[CH:7][CH:8]=5)=[CH:52][CH:53]=4)[C:10]4[CH:11]=[C:12]([N:35]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:13]=[CH:14][C:15]=4[C:16]4[C:21]3=[CH:20][C:19]([N: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)=[CH:18][CH:17]=4)=[CH:7][CH:8]=2)=[CH:20][CH:21]=1)=[CH2:14]
Reactant: COc1ccc(C2(c3ccc(OC)cc3)c3cc(N(c4ccccc4)c4ccccc4)ccc3-c3ccc(N(c4ccccc4)c4ccccc4)cc32)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: C=Cc1ccc(COc2ccc(C3(c4ccc(OCc5ccc(C=C)cc5)cc4)c4cc(N(c5ccccc5)c5ccccc5)ccc4-c4ccc(N(c5ccccc5)c5ccccc5)cc43)cc2)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
5.36 g (7.52 mmol) of 9,9-di(4-methoxyphenyl)-2,7-bis(diphenylamino)fluorene (Compound 2) is dissolved in 25 ml of dichloromethane and the solution cooled in a dry ice-acetone bath under the protection of flowing nitrogen. To this solution, 34 ml (34 mmol) of a 1.0 M solution of boron tribromide in dichloromethane is added dropwise while the reaction is stirred. After the addition of boron tribromide, the reaction mixture is allowed to warm to room temperature and is stirred at room temperature overnight. The reaction mixture is then poured into 300 g of crushed ice. Concentrated HCl (1.0 ml) is added and the aqueous mixture stirred at room temperature for 2 h. The mixture is then extracted with dichloromethane and the combined organic layer is dried over anhydrous magnesium sulfate. The solution is filtered and the solvent removed on a rotary evaporator. The crude product is re-dissolved in a small amount of ethyl acetate and purified on a silica gel column eluted by a mixture of ethyl acetate and hexane (9:1 v/v). After the solvent is removed, the solid is re-crystallized from the mixed solvent of ethanol and ethyl acetate to give 3.5 g of the final product as off-white crystals. Purity: 96.7 percent (HPLC)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:24])[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(O)c1ccncc1
Product: NC(=O)c1c(NC(=O)c2ccncc2)ncn1Cc1ccccc1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 19, using 1.00 g (4.62 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and isonicotinic acid instead of cyclopentylacetic acid to obtain 1.16 g of 1-benzyl-4-(4-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18](Cl)=[O:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:19]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: COC(=O)C1Cc2ccccc2N1C(=O)c1ccc(Cl)c(Cl)c1
Yield: 82.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 72A, methyl indoline-2-carboxylate (Lee, S. et al., Eur. J. Org. Chem., 38:459-471 (2003)) (3.23 g, 18.3 mmol) and 3,4-dichlorobenzoyl chloride (4.21 g, 20.1 mmol) were converted to the title compound (5.30 g, 83%) after purification using flash column chromatography (gradient from 0% to 5% EtOAc/CH2Cl2). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 7.67 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.41-7.37 (m, 1.5H), 7.23-7.20 (m, 1.5H), 7.04-7.01 (m, 2H), 5.31-5.08 (m, 1H), 3.77-3.75 (m, 3H), 3.62-3.55 (m, 1H), 3.24-3.19 (m, 1H); MS(ESI+) m/z 350.1 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:21]([C:52]1[N:53]=[CH:54][S:55][CH:56]=1)[C:22]([NH:24][CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:29]([CH2:32]Cl)[CH2:30][S:31][C@H:26]12)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:21]([C:52]1[N:53]=[CH:54][S:55][CH:56]=1)[C:22]([NH:24][CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:35])=[C:29]([CH2:32][S:1][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:30][S:31][C@H:26]12)=[O:23])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: Sc1ccc2nncn2n1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1cscn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3ccc4nncn4n3)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
6-Mercapto-1,2,4-triazolo[4,3-b]pyridazine (4.7 g) was added to a stirred suspension of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (5.0 g) and sodium iodide (4.6 g) in N,N-dimethylformamide (35 ml) and the mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and water and then the resultant mixture was adjusted to pH 7.5 with 20% aqueous solution of sodium carbonate. The separated organic layer was washed with saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The crude product obtained by concentration of organic layer was purified by silica gel column chromatography using ethyl acetate as an eluate. The fractions containing the object compound were evaporated to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.2 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:20][C:21]([NH:25][CH3:26])([CH3:24])[CH2:22]O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:21]([N:25]([CH3:26])[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH:11]([CH3:16])[C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:19])([CH3:24])([CH3:22])[CH3:20]
Reactant: CNC(C)(C)CO
Reactant: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1nc(C(=O)N(C)C(C)(C)C)ccc1C1CC1)C(F)(F)F

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid was reacted with 2-methyl-2-(methylamino)propan-1-ol (CAN 27646-80-6) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=345.4 [MH+].
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH:34]([C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2)=O>O1CCCC1.CCCCCC>[NH:40]1[C:41]2[C:37](=[C:36]([CH:34]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:28][CH:27]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:39]1
Reactant: Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(C=Cc2cccc3[nH]ccc23)cc1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
31 g of p-hydroxybenzyltriphenylphosphonium bromide ware suspended in 350 ml of tetrahydrofuran under an inert atmosphere, and over one hour 86 ml of a 1.6 M solution of butyllithium in hexane were added thereto. After stirring for 30 minutes, a solution of 5 g of 4-formyl-indole in 100 ml of tetrahydrofuran was added over 30 minutes, and the mixture was stirred for 24 hours. After dilution with 500 ml of water, the mixture was extracted with ethyl acetate. The fractions with an Rf=0.15 were isolated by chromatography on silica (eluent:methylene chloride) were triturated with petroleum ether (b.p. 60°-80° C.), filtered and dried under reduced pressure to obtain 7 g of 4-[(1H-indol-4-yl)-ethenyl]-phenol melting at ≃145° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]3[O:13][CH2:14][CH2:15][O:16][C:11]=3[C:10]([NH:17]C(=O)C)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]3[O:13][CH2:14][CH2:15][O:16][C:11]=3[C:10]([NH2:17])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(N2CCOCC2)c2c1OCCO2
Agent: Cl
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of N-(8-morpholino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (2 g, 7.19 mmol) in methanol (100 mL) was added concentrated Hydrochloric acid (5 mL) and then the mixture was stirred at room temperature overnight. After the solvent was removed under reduce pressure, water was added and the pH was adjusted to 7-8 using aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to afford the product 8-morpholino-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (1 g, yield 60%). 1H NMR (400 MHz, CDCl3) δ ppm 6.38-6.41 (d, 1H, J=8.4 Hz), 6.27-6.29 (d, 1H, J=8.4 Hz), 4.28-4.32 (m, 4H), 3.85-3.88 (t, 4H, J=4.8 Hz), 3.55 (s, 2H), 2.95-2.97 (t, 4H, J=4.8 Hz).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:32][CH2:31]1)[CH3:29]
Reactant: CCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Product: CCN1CCN(c2ccc(C(N)=O)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with 1-ethylpiperazin (0.83 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(4-ethylpiperazin-1-yl)nicotinamide. MS (Q1) 498.1 (M)+
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](Cl)=[O:43]>N1C=CC=CC=1>[CH2:15]([NH:14][C:12](=[O:13])[NH:11][C:8]1[S:9][C:10]2[C:2]([NH:1][C:42](=[O:43])[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ccccn3)c2s1
Yield: 67.9 %

Procedure:
Ethyl 1-(5-(7-amino-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (119 mg, 0.25 mmol) was dissolved in pyridine (2 ml) then picolinoyl chloride hydrochloride (58 mg, 0.33 mmol) was added with stirring and the reaction stirred at rt for 18 h. The pyridine was removed under reduced pressure and the residue triturated with water. The resulting solid was collected by filtration and dried to afford the crude product 100 mg (68%). This material was used directly in the next step without further purification.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:15][CH:14]([NH:16][C:17]([C:19]3[N:20]=[C:21]([N:24]4[CH2:27][CH:26]([S:28][C:29]5[C@H:30]([CH3:53])[C@@H:31]6[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]6[C:33]=5[C:34]([O:36]CC5C=CC([N+]([O-])=O)=CC=5)=[O:35])[CH2:25]4)[S:22][CH:23]=3)=[O:18])[CH2:13]2)=O)=CC=1)([O-])=O>O1CCCC1>[NH:12]1[CH2:15][CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([N:24]3[CH2:27][CH:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([OH:36])=[O:35])[CH2:25]3)[S:22][CH:23]=2)=[O:18])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NC5CN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)cs4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)NC5CNC5)cs4)C3)[C@H](C)[C@H]12
Reaction time: 4.5 h
Yield: 48.3 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[1-(p-nitrobenzyloxycarbonyl)-azetidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (490 mg, 0.617 mmol) (obtained as described in Example 59(1)) in a mixture of tetrahydrofuran (25 ml) and distilled water (25 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (490 mg) at room temperature for 4.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate and distilled water. The mixture was shaken in a separatory funnel. The aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→distilled water:acetonitrile (76:24)) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-(azetidin-3-ylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (143 mg, yield 49%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.[OH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36](Cl)=[C:37]([NH:42][CH:43]([CH3:45])[CH3:44])[N:38]=2)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36]([N:14]3[CH2:13][CH2:12][CH:11]([C:9]([C:7]4[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=4[F:17])=[O:10])[CH2:16][CH2:15]3)=[C:37]([NH:42][CH:43]([CH3:45])[CH3:44])[N:38]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:19]([OH:20])([C:21]([F:24])([F:23])[F:22])=[O:18]
Reactant: CC(C)Nc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Reactant: O=C(c1cc(Cl)ccc1F)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CN(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
A mixture of (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (69.7 mg, 0.251 mmol), 6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (90 mg, 0.209 mmol), sodium tert-butoxide (60.2 mg, 0.627 mmol), BINAP (19.5 mg, 0.031 mmol) and Pd2(dba)3 (9.6 mg, 10.4 μmol) in toluene (1.04 mL) was heated at 100° C. for 16 h. The mixture was purified by HPLC Method A to afford (1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanone as its TFA salt (48.9 mg, 36.8%) as a yellow oil. ESI-MS m/z [M+H]+ 523.4.