Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(#N)C.CO>[CH2:7]([O:6][CH2:5][C@H:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@H](CO)COCc1ccccc1
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@H](CO)COCc1ccccc1
Temperature: -10 °C
Reaction time: 20 h

Procedure:
(2R)-2-Amino-3-(benzyloxy)propan-1-ol (2.18 g) was dissolved in acetonitrile (38 ml) and methanol (7 ml), and triethylamine (2.0 ml) was added. The atmosphere was replaced with nitrogen, and then the mixture was cooled to −10° C. A solution of chloroacetyl chloride (1.05 ml) in acetonitrile (9 ml) was added dropwise thereto, and the mixture was stirred for 20 hours to be gradually warmed to room temperature. The reaction solvent was distilled off, and the residue was directly purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.26 g).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:31])=[O:24])=[CH:5][NH:6]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(OCCCO)cc3)c(F)c12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(OCCCO)cc3)c(F)c12
Temperature: 0 °C
Reaction time: 10 h
Yield: 43.2 %

Procedure:
To a mixture of 4,6-difluoro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde (30 mg, 0.1 mmol) in ACN/t-butanol=1/1(2 mL) was added 2-methyl-2-butene (0.5 mL) and cooled to 0° C. and added the aqueous solution of sodium chlorite (180 mg, 0.5 mL) and sodium dihydrogen phosphate (270 mg, 2 mmol) in water (0.5 mL) dropwise via additional funnel. The reaction was stirred at room temperature for 10 h. The reaction was quenched with sodium sulfite. The mixture was partioned between dichloromethane and water. The combined organics were concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (15 mg, 43%) as a white solid. MS (AP+) 348.1 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 7.36 (d, 2H), 7.03-6.98 (m, 3H), 4.14 (t, 2H), 3.77 (t, 2H), 2.04-2.01 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH2:21][NH2:22])[CH:14]=1)[CH:9]=2.[C:23](OC(=O)C)(=[O:25])[CH3:24].[C:30](O)(=[O:32])[CH3:31]>>[C:23]([NH:22][CH2:21][CH2:20][O:19][C:13]1[CH:12]=[CH:11][C:10]2[C:15]([CH:14]=1)=[N:16][C:17]1[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH:18]=1)[CH:9]=2)(=[O:25])[CH3:24]
Reactant: NCCOc1ccc2cc3ccc(OCCN)cc3nc2c1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCOc1ccc2cc3ccc(OCCNC(C)=O)cc3nc2c1

Procedure:
3,6-bis(2-aminoethoxy)acridine is treated with acetic anhydride/acetic acid followed by in vacuo removal of the volatiles, giving, after crystallization, the desired product.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C:5]2([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][O:3]1.FC(F)(F)C(O)=O>ClCCl>[C:19]1([CH2:18][C:5]23[CH2:4][O:3][C:2](=[O:1])[N:6]2[CH2:7][CH2:8][NH:9][CH2:10]3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2(Cc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC2(Cc3ccccc3)CNCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To 1,1-dimethylethyl tetrahydro-3-oxo-8a-(phenylmethyl)-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (2.8 g, 8.6 mmol) were added dichloromethane (40 mL) and trifluoroacetic acid (9.7 g, 86 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.74 g, yield 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A solution of [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.20 g, 0.58 mmol), iodomethane (Example 42, 0.14 g, 1.0 mmol) and K2CO3 (0.41 g, 3 mmol) in acetone (10 ml) was heated to reflux. After 2 hr, the reaction was cooled, filtered, concentrated to give an oil which was purified by column chromatography (eluent 10% EtOAc/hexane) to give a the desired product as a foam (0.10 g, Yield=48%); MS (ESI) m/z 408 ([M+H]+)
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)(=[O:26])[CH2:24][CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([N:27]1[CH2:28][CH2:29][CH:30]([C:33]([O:35][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:34])[CH2:31][CH2:32]1)(=[O:26])[CH2:24][CH3:25]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCC(=O)N1CCC(C(=O)O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 34.5 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1-propionyl-4-piperidinecarboxylic acid (5.5 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g), and by recrystallization in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 1-propionyl-4-piperidinecarboxylate (4.9 g), m.p. 189° C., is obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH2:21])=[NH:20])=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.CN(C)/[CH:24]=[CH:25]/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>COCCO>[CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:21]=[C:26]([C:28]4[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=4)[CH:25]=[CH:24][N:20]=3)=[CH:16][CH:17]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N=C(N)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Solvent: COCCO
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCC[C@@H]4C(=O)NC4CC4)cc3)n2)n1C(C)C
Temperature: 200 °C
Yield: 36 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 63; 0.29 g, 1.0 mmol) and ((2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one, (Method 24 of WO 03/076436; 0.15 g, 0.68 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. The solvent was removed in vacuo and the gum was carefully chromatographed eluting with DCM, 1% MeOH/DCM, 2% MeOH/DCM and finally 3% MeOH/DCM to yield a yellow solid (110 mg, 36%). NMR (299.954 MHz, CDCl3) 8.28 (d, 1H), 7.39 (d, 1H), 7.34 (s, 1H), 6.85-6.82 (m, 2H), 6.60-6.57 (m, 3H), 5.61 (septet, 1H), 3.96-3.92 (m, 1H), 3.62 (t, 1H), 3.19 (q, 1H), 2.76-2.67 (m, 1H), 2.56 (s, 3H), 2.30-2.22 (m, 2H), 2.07-1.84 (m, 2H), 1.47 (d, 6H), 0.78-0.70 (m, 2H), 0.45-0.38 (m, 2H); m/z 446.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(C1NC=CN=1)(C1NC=CN=1)=O.O.[NH2:28][NH2:29].Cl>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:28][NH2:29])=[O:5]
Reactant: NN
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 0.67 h
Yield: 93.1 %

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (1.0 g, 4.5 mmol) in THF (7 mL) was added carbonyl diimidazole (939 mg, 5.8 mmol). After 40 minutes, additional carbonyl diimidazole (200 mg, 1.2 mmol) was added and stirring was continued for 30 minutes. This solution was added dropwise to a separate flask containing hydrazine monohydrate (0.44 mL, 8.9 mmol) in THF (8 mL). After 1 h, 1M HCl was added, and the reaction mixture was extracted with 20% IPA/CHCl3 (×3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to afford the desired product as a white solid (1.0 g, 94%). MS (ESI): mass calcd. for C8H6ClF3N2O, 238.0; m/z found, 239.0 [M+H]+. 1H NMR (500 MHz, MeOD) δ 7.87 (dd, J=7.9, 1.3 Hz, 1H), 7.72-7.63 (m, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.05 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Oc1ccccc1CC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1ccc(OCC2CCCCC2)cc1
Yield: 54.6 %

Procedure:
To a solution of 4-bromophenol (6.0 g, 34.7 mmol), cyclohexylmethylphenol (4.3 ml, 34.7 mmol) and triphenylphosphine (9.1 g, 34.7 mmol) in tetrahydrofuran (100 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (15.1 ml, 34.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford 1-bromo-4-(cyclohexylmethoxy)benzene (5.1 g, yield: 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])C(OC)=O.[Cl-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h

Procedure:
2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120° C. (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product. (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105° C. 1H NMR (CDCl3) 8.3 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.12 (s, 2H), 3.60 (s, 3H). MS (FAB) m/z: 275.2 (M++1).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C(Cl)CCl.[CH:30]1[CH:35]=[N:34][C:33]2N(O)N=[N:38][C:32]=2[CH:31]=1.C(N(C(C)C)CC)(C)C.NC1C=NC=CC=1>CN(C=O)C>[O:1]=[C:2]1[N:6]2[C:7]([C:11]([NH:38][C:32]3[CH:33]=[N:34][CH:35]=[CH:30][CH:31]=3)=[O:13])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][N:3]1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)c1cccc2nn(CCc3ccc4ccccc4n3)c(=O)n12
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cccc2nn(CCc3ccc4ccccc4n3)c(=O)n12
Temperature: 40 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
In a 1-dram vial was placed 8-1 (15 mg, 0.045 mmol) in anhydrous DMF (0.45 mL). To this solution was added EDC (8.0 mg, 0.045 mmol), HOAT (6.0 mg, 0.045 mmol), diisopropylethylamine (0.008 mL, 0.045 mmol), and 3-aminopyridine (0.001 g, 0.049 mmol). The reaction mixture was heated at 40° C. and stirred for 16 h. The crude reaction mixture was then directly purified by reversed phase HPLC to give 15.0 mg (80%) of 8-2. 1H NMR (500 MHz, DMSO-d6): δ 11.06 (s, 1H), 8.84 (s, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.40 (d, J=5.0 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.79 (t, J=7.4 Hz, 1H), 7.64-7.55 (m, 2H), 7.53 (t, J=6.5 Hz, 1H), 7.32 (d, J=9.3 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.85 (d, J=6.5 Hz, 1H), 4.39 (t, J=7.6 Hz, 2H), 3.46 (t, J=7.6 Hz, 2H). HRMS (ES) 411.1546 (M+H) found, 411.1567 required.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12.C[Si](C)(C)NC(=O)C.CS([O:41][C:42](=O)[C:43]([C:52]1[N:56]=[C:55]([NH2:57])[S:54][N:53]=1)=[N:44][O:45][C:46]([C:49]([OH:51])=[O:50])([CH3:48])[CH3:47])(=O)=O.C(OCC)(=O)C>O1CCCC1>[NH2:57][C:55]1[S:54][N:53]=[C:52]([C:43](=[N:44][O:45][C:46]([C:49]([OH:51])=[O:50])([CH3:48])[CH3:47])[C:42]([NH:3][C@@H:4]2[C:27](=[O:28])[N:6]3[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]4[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=4)[CH2:9][S:10][C@H:5]23)=[O:41])[N:56]=1
Reactant: CC(C)(ON=C(C(=O)OS(C)(=O)=O)c1nsc(N)n1)C(=O)O
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
7β-Amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate dihydrochloride (181 mg) was suspended in tetrahydrofuran (9.1 ml). To the suspension was added N-(trimethylsilyl)acetamide (788 mg), and the mixture was stirred at 35° C. for 30 minutes and cooled to 5° C. To the resulting solution was added a solution of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic methanesulfonic anhydride (syn isomer) (169 mg) in tetrahydrofuran (0.5 ml). The mixture was warmed to 2° C. and stirred for 1.2 hours. The mixture was poured into ethyl acetate (200 ml) and the resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was suspended in water (40 ml) and adjusted to pH 1 with 1N hydrochloric acid. After the insoluble materials were removed by filtration, the filtrate was chromatographed on Diaion HP-20 (15 ml) and the elution was carried out with 15% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (120 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[OH2:12].O.Cl[Sn]Cl.[CH2:17]([OH:19])[CH3:18]>>[I:11][C:9]1[CH:10]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][C:17](=[O:19])[C:18](=[O:12])[NH:1]2
Reactant: CCO
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: O
Agent: Cl[Sn]Cl
Product: O=c1[nH]c2ccc(I)cc2[nH]c1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Synthesis of 6-1-do-1,4-dihydro-2,3-quinoxalinedione: The procedure of Foged, C. and Journal, P. (J. of Lab. Compd. and Radiopharmac. XXXI (5):365-373 (1992)) was adapted. To a stirred mixture of 2-nitro-4-iodoaniline (1.8 g, 6.9 mMol) in ethanol (40 mL) was added SnCl2.2H2O (7.8 g, 34.6 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 0.5 h to form a clear solution and the reflux was continued for another 1.5 h. The solution was cooled to room temperature and ice water (100 g) was added. The pH was adjusted to pH~7 and the mixture was extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated to dryness to give 1.235 g (78%) of title compound as a brown solid. To a stirred mixture of this product (450 mg, 1.92 mMol) in 4N HCl (20 mL) was added oxalic acid (267 mg, 2.115 mMol, used as received) in one portion. The mixture was refluxed at 120°-5° C. for 3 h, then cooled to room temperature overnight. The mixture was centrifuged and the red precipitate was washed with cold water (2×2 mL), collected by filtration and dried at 60° C. at reduced pressure for 2 h, affording 140 mg (25%) of crude product as a white powder. The sample was dissolved in 1N NaOH (10 mL), filtered, and the filtrate was acidified to pH=6, affording 130 mg of product which was washed with EtOH (2 mL). Crystallization from DMSO/H2O gave 19 mg of pure title compound as white microcrystals, mp: 355°-7° C. IR (KBr, cm-1) 3459, 3148, 1750, 1704, 1392. NMR (1H, DMSO-d6): δ6.727 (d, J=8.1 Hz, 1H), 7.053 (dd, J1 =1.8 Hz, J2 =8.4 Hz, 1H), 11.952 (s, 1H), 11.998 (s, 1H). HRMS: calcd for C8H5N2O2I (M+) m/z 287.9393. Found: 287.9390. Potency relative to DCK: 4.7%.
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1>C(O)C>[NH2:8][C:7]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:3]([S:4][CH3:5])[C:6]=1[C:9]#[N:10]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: CSc1nc2ccnn2c(N)c1C#N
Temperature: 25 °C
Yield: 88.3 %

Procedure:
10.3 g of bismethylthio methylenepropane dinitrile, 5.0 g of 3-aminopyrazole and 250 ml of ethanol were stirred under reflux with heating for about 6 hours and then cooled to room temperature, and the precipitated crystals were collected by filtration. The collected crystals were washed with ethanol and then dried to obtain 10.9 g of 7-amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 1) having a melting point of at least 240° C.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][C@@H:13](/[CH:15]=[CH:16]/[P:17]([O:22]CC)([O:19]CC)=[O:18])[O:12][C@H:11]1[N:25]1[C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=2[N:27]=[N:26]1)(=O)C1C=CC=CC=1.C(NC1NC(=O)C2N=CN(C3C(OC(=O)C4C=CC=CC=4)CC(C=CP(O)(O)=O)O3)C=2N=1)(=O)C>>[NH2:34][C:33]1[C:28]2[N:27]=[N:26][N:25]([C@@H:11]3[O:12][C@H:13](/[CH:15]=[CH:16]/[P:17](=[O:18])([OH:19])[OH:22])[CH2:14][C@H:10]3[OH:9])[C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: CCOP(=O)(/C=C/[C@@H]1C[C@@H](OC(=O)c2ccccc2)[C@H](n2nnc3c(N)ncnc32)O1)OCC
Agent: CC(=O)Nc1nc2c(ncn2C2OC(C=CP(=O)(O)O)CC2OC(=O)c2ccccc2)c(=O)[nH]1
Product: Nc1ncnc2c1nnn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)C[C@H]1O
Yield: 76.2 %

Procedure:
Compound 38.2 (60 mg, 68% yield) was synthesized from compound 38.1 (115 mg, 0.24 mmol) using the procedure described for the preparation of compound 9.10. 1H NMR (D2O, 300 MHz): δ 2.31-2.55 (m, 2H), 4.78-4.98 (m, 2H), 5.78-5.88 (m, 1H), 5.94-6.08 (m, 1H), 6.23 (s, 1H). 31PNMR: 9.20 ppm. LRMS C10H13N6O5P requires 327.1. Found 327.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[CH3:22]CN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33].Cl>ClCCl>[F:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]2[C:31]([O:32][CH3:33])=[O:34])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CCNC(c2ccc(C(F)(F)F)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
2-(3-Fluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (3.12 g, 10.22 mmol) was dissolved in dichloromethane (50 mL), then DIPEA (4.45 mL, 25.55 mmol) and methyl carbonochloridate (0.966 mL, 12.26 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M HCl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated to yield dimethyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (3.2 g, 86%). MS m/z 364 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[C:13](NC1C=CC(C(O)=O)=CC=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Product: COc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-Amino-3-methoxybenzoic acid (1 g, 5.98 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting solid was recrystallized from ethyl acetate and hexanes to provide the desired product (1.5 g) as tan crystals: m.p. 176-178° C.; 1H NMR (CD3OD) δ 1.52 (9H, s), 3.92 (3H, s), 7.56 (1H, s), 7.62 (1H, d, J=8.4 Hz), 7.96 (1H, s), 8.03 (1H, d, J=8.4 Hz); 13C NMR (CD3OD) δ 28.53, 56.35, 81.78, 112.01, 118.58, 124.20, 125.76, 133.84, 149.04, 154.20, 169.60; HRMS Calc. for C13H17NO5, 267.1107; Found, 267.1103.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](O)[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C@@H]1[C@@H](OCC2C=CC=CC=2)[C@@H](OC(F)(F)F)[C@@H](C(=S(=O)=O)OCC2C=CC=CC=2)O[C@@H]1OC)C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:36]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CO[C@H]1O[C@H](C(OCc2ccccc2)=S(=O)=O)[C@H](OC(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OS(=O)(=O)C(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 mL) in methylene chloride (17.5 mL) cooled to -15° C. was added trifluoromethane sulfonic anhydride (0.87 mL). The mixture was stirred during 15 min at -10° C., then methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 mL) was added (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull. Chem. Soc. Jpn, 56, 2849 (1983)). The mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil which was the expected triflate methyl 2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D -galactopyranoside (1.43 g, 93%).