Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C@@H:9]1[O:13][C@:12]([CH3:24])([O:14][CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[C@@H:11]([OH:25])[C@H:10]1[OH:26].NC1N=CN=C2C=1N=CN2[C@@H]1O[C@](C)(OCP(=O)(O)O)[C@@H](O)[C@H]1O>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C@@H:9]1[O:13][C@:12]([CH3:24])([O:14][CH2:15][P:16](=[O:17])([OH:23])[OH:20])[C@@H:11]([OH:25])[C@H:10]1[OH:26]
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O)OCC
Agent: C[C@]1(OCP(=O)(O)O)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: C[C@]1(OCP(=O)(O)O)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 75.2 %

Procedure:
Compound 32.4 (61 mg, 75% yield) was synthesized from compound 32.2 (95 mg, 0.24 mmol) using the procedure described for the preparation of compound 31.5. 1H NMR (300 MHz, D2O) δ 1.38 (s, 3H), 3.50 (m, 2H), 3.98 (d, 1H, J=4.6), 5.84 (d, 1H, J=7.6), 6.08 (d, 1H, J=7.3), 7.81 (d, 1H, J=8.2). LRMS [M-H]− C10H15N2O9P requires 337.2. Found 337.2.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[CH:39]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(F)c1)N1CCN(C2CCCC2)CC1
Yield: 78 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-fluorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[OH:52][C:51]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[O:17][C:48](=[O:49])[C:47]=1[S:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH:37]([CH3:39])[CH3:38]
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCc3cccnc3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-(pyridin-3-ylmethoxy)acetophenone (1.09 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22 mmol) m.p. 225° C.; ; 1H NMR (400 MHz, DMSO-d6) δ 1.23 (d, 6H), 3.41 (m, 1H), 5.26 (s, 2H), 6.78 (s, 1H), 6.90 (d, 1H), 7.08 (dt, 2H), 7.21 (d, 2H), 7.29 (d, 1H), 7.45 (dd, 1H), 7.82 (d, 2H), 7.91 (d, 1H), 8.56 (d, 1H), 8.71 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2cccnc2)CC1
Yield: 85.9 %

Procedure:
To a solution of COMPOUND 249 (65 mg, 0.21 mmol) in THF (2 mL) was added nicotinoyl chloride hydrochloride (60 mg, 0.34 mmol) followed by DIPEA (0.10 mL, 0.57 mmol). The resultant mixture was stirred at room temperature for 40 minutes. The mixture was treated with 1.0 N NaOH (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2-MeOH—NH4OH) provided 75 mg (86%) of COMPOUND 265 as a white solid. 1H NMR (CDCl3) δ 1.61-1.75 (m, 2H), 1.90-1.99 (m, 2H), 2.09 (s, 6H), 2.55-3.00 (m, 3H), 3.75-3.90 (m, 5H), 4.75-4.80 (m, 1H), 7.09 (dd, 2H, J=7.5, 4.8 Hz), 7.34-7.39 (m, 3H), 7.75 (dt, 1H, J=6.0, 1.8 Hz), 8.35 (d, 2H, J=4.8 Hz), 8.65 (s, 2H); ES-MS m/z 416 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH3:10])=[CH:3][CH:2]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>C(N(CC)CC)C>[CH2:9]([N:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:11](=[O:14])[CH:12]=[CH2:13])[CH3:10]
Reactant: C=CC(=O)Cl
Reactant: CCNCc1ccncc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CC)Cc1ccncc1

Procedure:
Following the method of Example 3, 4-picolyl-ethylamine (4.27 g, 0.035 mole) was reacted with acryloyl chloride (3.15 g, 0.035 mole) was triethylamine (21 ml) and purified by chromatography on silica.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18]C)=[CH:4][CH:3]=1.O>CS(O)(=O)=O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Temperature: 110 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 29 g of 9-fluoro-6-methoxybenzo[g]iso-quinolin-5,10-dione in 145 ml of methanesulfonic acid is heated at 110° C., with stirring and under inert gas atmosphere, for about 2 hours, then added to 3000 ml of water. After 1 hour under stirring, the formed precipitate is filtered, washed with about 300 ml of water, taken up into a further 2000 ml of water and, after stirring for 30 minutes, filtered again. The mother liquors are extracted with 500 ml of ethyl acetate. The organic phase is separated and the solvent is evaporated under reduced pressure. The residue (3 g) is combined with the first crystallization crop and the whole is taken up into 500 ml of isopropanol. After an hour under stirring, the crystallized product is filtered, to obtain 24.16 g of product, m.p. 189-192° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][C:12]2=[O:23])C1C=CC=CC=1.CC1CC=CCC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][C:12]2=[O:23]
Reactant: COC(=O)CC1CC(=O)c2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: COC(=O)CC1CC(=O)c2cc(O)ccc21
Temperature: 55 °C

Procedure:
To a solution of methyl [5-(benzyloxy)-3-oxo-2,3-dihydro-1H-inden-1-yl]acetate (1.0 g, 3.22 mmol) and 1-methylcyclohexa-1,4-diene (10 ml, 89 mmol) in ethanol (30 ml) was added 10% Pd/C (0.686 g, 0.644 mmol), and the mix was stirred at 55° C. After 1 hour the mix was filtered through a bed of Celite, washing with ethanol The filtrate was concentrated and the residue was concentrated from ether-hexane to give methyl (5-hydroxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate. LC-MS for C12H12O4: calc 220, found 221 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](OS(OCC)(=O)=O)[CH3:15].C(N(CC)CC)C>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CCOS(=O)(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(N)cccc1[N+](=O)[O-]

Procedure:
A solution of 2-amino-6-nitrobenzoic acid (29.2 g, 0.16 mol), diethylsulfate (24.7 g, 0.160 mol) and triethylamine (16.2 g, 0.160 mol) in N-dimethylformamide (250 ml) was stirred at 20-25° for 20 hours. After removing DMF at 60° and 0.2 mm pressure, the residue was flash chromotographed over silica gel and the ethyl ester (10.8 g) eluted first with toluene then with 50% toluene-50% chloroform.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]3[C:29]([O:31][CH3:32])=[O:30])[C:7]=2[CH:33]=1)#[N:2].FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[C:29]([O:31][CH3:32])=[O:30])[C:7]=2[CH:33]=1)#[N:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCN1C(=O)COc2ccc(C#N)cc21
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CNCCC1CCCN1C(=O)COc2ccc(C#N)cc21

Procedure:
A solution of 1-tert-butyl 3-methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-1,3-dicarboxylate (Intermediate 131, 220 mg, 0.48 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[C:3]=1[F:23]>CO.[Pd]>[F:23][C:3]1[C:4]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2
Reactant: COc1ccc2nc(-c3ccc(C(=O)O)cc3)c(F)c(Cl)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3)c(F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of the mixture from Step 1 in absolute MeOH (5 mL) was added Pd/C (10% Pd, 100 mg). The mixture was stirred at 25° C. for 1 hour under H2 atmosphere. The solids were filtered off and the filtrate was concentrated to give the product (60 mg, two-step yield 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.FC(F)(F)C(O)=O.NC1C(C2C=CC(CC(N)=O)=CC=2)=C(OC2C=CC(NC(NC(=O)CC3C=CC(F)=CC=3)=O)=CC=2F)C=CN=1.[NH2:57][C:58]1[CH:63]=[C:62]([F:64])[C:61]([OH:65])=[C:60]([F:66])[CH:59]=1>>[NH2:57][C:58]1[CH:63]=[C:62]([F:64])[C:61]([O:65][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=2)=[C:60]([F:66])[CH:59]=1
Reactant: Nc1cc(F)c(O)c(F)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: NC(=O)Cc1ccc(-c2c(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccnc2N)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(Oc2c(F)cc(N)cc2F)ccn1
Yield: 28.9 %

Procedure:
4-Chloropicolinamide (0.47 g, 3.0 mmol) was converted to the title compound (0.23 g, 29%) in a manner similar to the preparation of Compound C of Example 112, except that 4-amino-2,6-difluorophenol (0.44 g, 3.0 mmol) was used instead of 4-amino-2,5-difluorophenol. 1H NMR (DMSO-d6) δ 8.60 (d, 1H, J=5.6 Hz), 8.22 (br s, 1H), 7.83 (br s, 1H), 7.45-7.46 (m, 1H), 7.30-7.32 (m, 1H), 6.43-6.49 (m, 2H), 5.94 (s, 2H); MS(ESI+) m/z 266 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](=[S:17])[NH2:16])=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:21][CH2:22][C:23]1[N:16]=[C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=4[C:7](=[O:19])[N:8]([CH3:18])[CH2:9][C:10]=23)[S:17][CH:24]=1
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)cc2C1=O
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Yield: 57.4 %

Procedure:
A suspension of 4.51 g (0.0155 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide in 100 ml of dioxan was treated with 2.16 g (0.0171 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 41 hrs., cooled and completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from hot ethyl acetate. There were obtained 3.23 g (57%) of 3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 239-241°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>ClCCl>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Oc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenoxy)-2,4-dimethylquinolin-5-ol (0.16 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.20 g) and bromoacetic acid methyl ester (0.88 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 5:1 by volume) gave title compound as an off-white solid, 0.20 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(O)(C)C.CCOCC.O>[ClH:1].[ClH:14].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: Clc1ccc(CN2CCN(c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 1-(4-chlorophenyl)piperazine (1.61 g, 0.01 mole), 4-chlorobenzyl chloride (2.10 g, 0.01 mole) and potassium carbonate (2 g) in acetonitrile (40 mL) is heated at reflux for 6 hours under a nitrogen atmosphere. After cooling, the reaction mixture is poured into water (50 mL) and ether (50 mL). The aqueous layer is discarded and the organic layer is extracted with 1 N aqueous hydrochloric acid solution. The acidic extract is neutralized with 6 N ammonium hydoxide solution and extracted with ether. The organic layer is dried (Na2SO4) and concentrated to provide the crude free base of the desired unsymmetrically substituted piperazine. This material is dissolved in warm isopropanol (10 mL) and treated with a 1 N solution of HCl in ether until acidic to pH paper. Upon cooling, crystals of dihydrochloride salt are collected (2.2 g, 56%).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:14]=[C:13]([NH:15][P:16]([O:20][CH3:21])([O:18][CH3:19])=[O:17])[S:12][N:11]=1)[C:7]([O-:9])=O)[CH:2]=[CH2:3].[Na+].C(=O)(O)[O-].[Na+].CS(Cl)(=O)=O.Cl.Cl.[NH2:35][CH:36]1[C:53](=[O:54])[N:38]2[C:39]([C:50]([O-:52])=[O:51])=[C:40]([CH2:43][N+:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:41][S:42][C@H:37]12.C[Si](CC(N)=O)(C)C.Cl>CN(C)C(=O)C.C(Cl)Cl>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:14]=[C:13]([NH:15][P:16]([O:20][CH3:21])([O:18][CH3:19])=[O:17])[S:12][N:11]=1)[C:7]([NH:35][CH:36]1[C:53](=[O:54])[N:38]2[C:39]([C:50]([O-:52])=[O:51])=[C:40]([CH2:43][N+:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:41][S:42][C@H:37]12)=[O:9])[CH:2]=[CH2:3]
Reactant: NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12
Reactant: C=CCON=C(C(=O)[O-])c1nsc(NP(=O)(OC)OC)n1
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NP(=O)(OC)OC)n1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
To a suspension of sodium 2-allyloxyimino-2-[5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl]acetate (syn isomer) (358.5 mg) and sodium bicarbonate (42 mg) in N,N-dimethylacetamide (3.6 ml) was added dropwise methanesulfonyl chloride (172 mg) under cooling in an ice bath and stirring, which was continued for 1.5 hours at the same temperature. On the other hand, a mixture of 7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrochloride (400 mg) and trimethylsilylacetamide (2 g) in methylene chloride (4 ml) was stirred at room temperature to give a solution and cooled to -30° C. The cold solution was added to the activated mixture prepared above and the resulting mixture was stirred for 30 minutes at -20° to -15° and then for additional 20 minutes at -15° to 0° C. The mixture was poured into 6% aqueous solution of sodium bicarbonate (5 ml), adjusted to pH 3 with 6N hydrochloric acid and evaporated to remove methylene chloride. The residual aqueous solution was diluted to 72 ml with water and subjected to column chromatography on a nonionic adsorption resin "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries) (36 ml). After the column was washed with water, the elution was carried out with 30% and 40% aqueous methanol successively. The fractions containing the object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-allyloxyimino-2-{5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl}acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (379 mg), mp. 157° to 165° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[CH3:10])[C:5]([NH2:22])=[N:4][CH:3]=1.BrC1N=C2N(CC3C=C4C(=CC=3)N=CC=C4)N=NC2=[N:26]C=1>>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[CH3:10])[N:26]=[N:22][C:5]2=[N:4][CH:3]=1
Reactant: CC(Nc1nc(Br)cnc1N)c1cc2cccnc2cc1F
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: CC(c1cc2cccnc2cc1F)n1nnc2ncc(Br)nc21

Procedure:
The title compound was prepared from 6-bromo-N2-(1-(7-fluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine in analogy to the synthesis of compound 52.2. LCMS (method B): [MH]+=345, tR=2.36 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[C:60]([Cl:62])[CH:59]=[C:58]([Cl:63])[CH:57]=2)=[O:53])[CH2:48][CH2:47]1>CN(C=O)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]([NH:42][CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[C:60]([Cl:62])[CH:59]=[C:58]([Cl:63])[CH:57]=3)=[O:53])[CH2:48][CH2:47]2)=[O:8])[N:3]=[N:2]1
Reactant: NCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1c[nH]nn1
Reaction time: 0.17 h

Procedure:
To 1H-1,2,3-triazole-4-carboxylic acid (32.7 mg, 0.289 mmol) in DMF (2 ml) was added HATU (110 mg, 0.289 mmol) and DIPEA (0.050 ml, 0.289 mmol). The resulting yellow solution was stirred for 10 mins and treated with 3,5-dichlorobenzyl 4-(3-amino propyl)piperazine-1-carboxylate (step 2) (100 mg, 0.289 mmol). After stirring at ambient temperature for 4 hrs, the mixture was diluted with EtOAc (50 ml) and washed with water (2×10 ml). The organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in DCM and applied to a 20 g silica cartridge eluting with 10% MeOH/DCM containing 1% aqueous 880 ammonia. The product fractions were concentrated to give 3,5-dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate as a white foam;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C@@H:9]1[C:15](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:16].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:9]([CH2:15][OH:16])[N:10]([CH3:14])[C:11](=[O:13])[CH2:12]1
Reactant: CN1C(=O)C[C@@H](c2ccccc2F)[C@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@@H](c2ccccc2F)[C@H]1CO
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a −78° C. solution of (4S)-3-{[(2S,3S)-3-(2-fluorophenyl)-1-methyl-5-oxopyrrolidin-2-yl]carbonyl}-4-benzyl-1,3-oxazolidin-2-one (1.0 g, 2.5 mmol) in anhyd. THF (30 mL) was added a solution of LiAlH4 (1M in THF, 2.5 mL, 2.5 mmol, 1 equiv). After 2 h a solution of LiAlH4 (1M in THF, 0.5 mL, 0.5 mmol, 0.2 equiv) was added and after 30 min the reaction was treated with a saturated NH4Cl solution (10 mL). The resulting mixture was allowed to warm to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (50 g silica gel, gradient from 0% to 10% MeOH/EtOAc) to afford (4S,5S)-4-(2-fluorophenyl)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (340 mg, 61%) as a white solid: TLC (5% MeOH/EtOAc) Rf 0.40; 1H NMR (CDCl3) δ 2.41 (dd, J=8.4, 15.8 Hz, 1H), 2.94 (s, 3H), 3.03 (dd, J=11.6, 16.0 Hz, 1H), 3.21 (dd, J=2.2, 12.5 Hz, 1H), 3.53 (br s, 1H), 3.67 (dd, J=2.2, 12.5 Hz, 1H), 3.81-3.85 (m, 1H), 3.94-4.03 (m, 1H), 7.04 (t, J=9.0 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.22-7.29 (m, 1H), 7.38 (t, J=7.5 Hz, 1H); HPLC ES-MS m/z (rel abundance) 224 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[C:11]([CH3:24])[CH:10]=2)[N:3]=1.Br[C:26]1[S:30][CH:29]=[N:28][CH:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([C:26]3[S:30][CH:29]=[N:28][CH:27]=3)[CH:12]=[C:11]([CH3:24])[CH:10]=2)[N:3]=1
Reactant: Brc1cncs1
Reactant: Cc1cc(Nc2nccc(C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2nccc(C)n2)cc(-c2cncs2)c1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
A microwave vial was charged with Intermediate 18 (218 mg, 0.670 mmol), 5-bromo-1,3-thiazole (59.9 μL, 0.670 mmol), Pd2(dba)3 (30.7 mg, 0.034 mmol), X-Phos (32.0 mg, 0.067 mmol) and cesium carbonate (437 mg, 1.341 mmol). The system was purged and flushed with Ar(g) four times before adding dioxane (918 μL) and water (92 μL). Again, the system was purged and flushed five times before sealing the vial and heating at 100° C. LCMS showed ˜60% desired product, ˜35% de-borolated product and remaining unreacted starting material. The reaction mixture was diluted with ethyl acetate, filtered through a celite plug and concentrated. The resultant residue was purified by column chromatography on silica gel (Biotage, 0-20% ethyl acetate in hexanes) to afford 4-methyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (105 mg, 0.372 mmol, 55.5%). MS ESI: [M+H]+ m/z 283.0. 1H NMR (500 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.04 (s, 1H), 8.35 (d, J=6.6, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.10 (s, 1H), 6.75 (d, J=6.3, 1H), 2.37 (s, 3H), 2.30 (s, 3H).