Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1N=[CH:9][CH:8]=[CH:7]2.N1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C(O)C>[C:6]1([CH:7]=[CH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=[CH:2][CH:11]=1
Reactant: C1CCNCC1
Reactant: Oc1cccc2cccnc12
Solvent: O
Solvent: CCO
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Complex II-1 was synthesized through a reaction in the ethanol solution of 8-hydroxyquinoline, 2,2′-diol-stilbene (L3) and GaCl3. First, a solution of 8-hydroxyquinoline (0.05M) and piperidine (0.05M) in 100 ml ethanol was added to a solution of GaCl3 (0.5M) in 10 ml ethanol very slowly with an intensive stirring. Then, a solution of L3 (0.01M) and piperidine (0.02M) in 500 ml ethanol was introduced slowly. The mixture was stirred for about 1 hour and cooled to room temperature and kept in dark for about 1 hour. A scarlet precipitate was formed when equivalent amount water was poured into the solution. The product was collected by filtration and washed with ethanol rapidly, then dried under an infrared lamp. The obtained product powder showed strong red fluorescence under an ultraviolet lamp. The materials were further purified by an improved train sublimation method. The L3 ligand was obtained by typical synthesis method of stilbene. The molecular structure of Complex II-I was supported by mass spectrum (MS) and element analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][C:28]([F:31])=[CH:29][CH:30]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Li+]>CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][C:28]([F:31])=[CH:29][CH:30]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 0.1 %

Procedure:
To N-[(4aR,7aR)-6-(5-fluoropyrimidin-2-yl)7a-(5-fluorothiophen-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (391 mg, 855 mmol) is added methanol (8.5 mL) and lithium hydroxide (179 mg, 4.27 mmol). The solution is heated to reflux for 2.5 hours under an atmosphere of nitrogen. The resulting solution is allowed to cool for a few minutes then concentrated under reduced pressure. The residue is extracted with dichloromethane (30 mL) and water (30 mL). The phases are partitioned and the aqueous phase further extracted with dichloromethane (1×30 mL). The combined dichloromethane extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol, gradient from 99:1 to 90:10, to give the title compound (263 mg, 87%) as an amorphous white foam. ES/MS (m/e): 354.0 (M+H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C@@H:16]1[C@@H:20]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:19][C@H:18]([O:30][CH3:31])[C@:17]1([CH3:33])[OH:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C.O>[CH2:34]([O:32][C@:17]1([CH3:33])[C@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:20]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:19][C@@H:18]1[O:30][CH3:31])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
1.2 g of sodium hydride was added to an N,N-dimethylformamide solution of 7.2 g of (2S,3R,4R,5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolan-3-ol, and thereafter, 5.1 g of benzyl bromide was added dropwise to the mixture at a temperature of 15° C. or lower. The obtained mixture was stirred at room temperature for 1.5 hours. Thereafter, 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with 200 mL of 1 mol/L hydrochloric acid and 200 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure, so as to obtain 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolane in the form of a colorless oily product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]2[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].[NH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:31]1[CH:36]=[C:35]([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:34]=[CH:33][CH:32]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 80 °C

Procedure:
To a mixture of tetrakis(triphenylphosphine)palladium (0) (0.12, 0.1 mmol), 2N sodium carbonate (5 mL, 10 mmol), [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (from Example 1, 0.67 g, 2.0 mmol) in 20 mL of toluene and 5 mL of ethanol was added 3-aminobenzeneboronic acid (0.62 g, 4.0 mmol). The reaction mixture was heated to 80° C. for 1 hour, diluted with ethyl acetate, washed with water and dried over MgSO4. Removal of solvent under reduced pressure gave a crude product that was purified by silica gel chromatography eluting with ethyl acetate/hexanes (5% to 50%) to give the title compound as a pale yellow solid; MS (EI) m/z 393.3 (M+H)+; 1H NMR (DMSO-d6): δ 5.21 (s, 2H), 6.39 (d, J=8.8 Hz, 1H), 6.47 (s, 1H), 6.48 (d, J=9.4 Hz, 1H), 6.95 (t, J=9.4 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.56 (t, J=8.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.80 (t, J=7.8 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.31 (d, J=6.7 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[C:2]([F:1])[CH:3]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nccn1-c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
3-Fluoro-4-(2-methylimidazol-1-yl)nitrobenzene (40 g, 0.181 M) was dissolved in a mixture of methanol (200 ml) and tetrahydrofuran (800 ml), cooled to 0° under nitrogen, and treated with ammonium formate (57 g, 0.905 M) followed by palladium on charcoal (10%, 2 g). The mixture was stirred at ambient temperature for 18 hours, filtered through celite, celite washed with methanol (100 ml), and filtrate evaporated to dryness. The residue was partitioned between ethyl acetate (800 ml) and 10% aqueous sodium bicarbonate (250 ml). The organic layer was separated, washed with brine (250 ml), dried (magnesium sulfate) and evaporated to give title compound (34.6 g). NMR (DMSO-d6) δ: 2.08 (s, 3H); 5.68 (s, 2H); 6.45 (overlapping m, 2H); 6.84 (d, 1H); 7.03 (overlapping m, 2H). MS (ESP): 192 (MH+) for C10H10FN3
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:7]1)=[O:5])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:25]=[C:24]2[C:38](O)=[O:39].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[OH-].[Na+]>ClCCl>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:13][CH2:14][N:15]([C:38]([C:24]3[C:23]4[C:28](=[CH:29][CH:30]=[C:21]([Cl:20])[CH:22]=4)[N:27]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH:25]=3)=[O:39])[CH2:16][CH2:17]2)[CH2:7]1)=[O:5])[CH3:19]
Reactant: CCN(CC)C(=O)C1CCCN(C2CCNCC2)C1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)nc2ccc(Cl)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C1CCCN(C2CCN(C(=O)c3cc(-c4ccc(Cl)cc4)nc4ccc(Cl)cc34)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.2 %

Procedure:
To a solution of [1,4′]bipiperidinyl-3-carboxylic acid diethylamide (0.38 mmol, 115 mg) and 6-chloro-2-(4-chloro-phenyl)-quinoline-4-carboxylic acid (0.417 mmol, 133 mg) in anhydrous dichloromethane was added 1-hydroxybenzotriazole hydrate (0.42 mmol, 56 mg) followed by triethylamine (1.52 mmol, 0.8 mL) then 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.46 mmol, 87 mg). The solution was stirred at ambient temperature for 16 hr then 2M sodium hydroxide (25 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was chromatographed on a silica gel rotor eluting with a 1 to 5% methanol in dichloromethane gradient to give the title compound (63 mg, 29%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:14][C:15](OCC)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)[CH2:14][CH2:15][OH:16]
Reactant: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 215 mg (0.51 mmol) of the compound from Example 25A was added dropwise to 1.8 ml (1.80 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran under argon in 10 ml of tetrahydrofuran at RT. The mixture was stirred at RT for 15 min and then, while cooling in ice, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) resulted in 169 mg (87% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:7]=1.[Cl:16]N1C(=O)CCC1=O>C(#N)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:16])[C:5]2=[O:15])=[N:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-n2cc(Cl)ccc2=O)nc1
Solvent: CC#N
Product: Cc1ccc(-n2cc(Cl)cc(Cl)c2=O)nc1

Procedure:
A solution of 5-Chloro-5'-methyl-[1,2']bipyridinyl-2-one from example 10 Step 1(2.00 g, 4.53 mmol) and N-chlorosuccinimide (1.21 g, 9.06 mmol) in acetonitrile (25 mL) was heated at reflux for 4 hrs. The solvent was evaporated in vacuo and the residue chromatographed (silica gel, EtOAc: CH2Cl2 10:90 to 30:70 gradient elution) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCCC1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: Nc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc([N+](=O)[O-])ccc1Nc1ccccc1
Yield: 88 %

Procedure:
2-Chloro-5-nitrobenzonitrile (Aldrich) (3.64 grams (hereinafter “g”), 20 millimoles (hereinafter “mmol”), aniline (2 milliliter (hereinafter “mL”), 22 mmol), N-methylpyrollidine (10 mL) and diisopropylethylamine (4 mL) were combined and heated to 120° under Ar for 18 hours (hereinafter “h”), cooled, poured into EtOAc (150 mL), washed with H2O (3×50 mL) and saturated aqueous (hereinafter “satd. aq.) NaCl (50 mL), dried (Na2SO4), concentrated, and the residue was triturated with hexane, filtered and the solid was washed with hexane and dried in vacuo to afford 4.23 g (88%) of the title compound as a light green solid. 1H NMR (400) MHz, δ: 8.45 (finely split doublet, 1), 8.19 (dd, 1), 7.48 (m,3), 7.28 (d,2), 7.06 (d, 1), 6.96 (br s,1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(OP(Cl)(=O)OCC)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([OH:27])=[C:21]([CH2:28][CH3:29])[CH:20]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:18][C:19]1[CH:20]=[C:21]([CH2:28][CH3:29])[C:22]([OH:27])=[C:23]([CH2:25][CH3:26])[CH:24]=1)=[O:8]
Reactant: CCc1cc(N)cc(CC)c1O
Reactant: O=C(O)c1cccs1
Agent: CCOP(=O)(Cl)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(NC(=O)c2cccs2)cc(CC)c1O
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Under ice-cooling, 128 mg of 2-thienylcarboxylic acid is dissolved in 3 ml of acetonitrile, and to the resultant solution are added 303 mg of triethylamine, then 207 mg of diethylphosphorochloridate. After the mixture is stirred for 30 minutes, 201 mg of 4-amino-2,6-diethylphenol is added and the reaction mixture is stirred at room temperature. After completion of the reaction, ice chips are added, and then an aqueous 5 % sodium hydrogen carbonate is added. The crystals precipitated are collected by filtration, washed with isopropyl ether and the residue is recrystallized from ethyl acetate to give 150 mg of 4-(2-thienylcarbonyl)amino-2,6-diethylphenol as white crystals.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@H:28]2[CH3:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)#[N:2].CS(C)=[O:44].OO.[OH-].[Na+]>CO.CC#N>[C:1]([C:3]1[N:4]=[CH:5][C:6]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C@H:28]2[CH3:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:44])[NH2:2]
Reactant: CS(C)=O
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)CCCN1c1cnc(C(N)=O)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
tert-Butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (312) (430 mg, 0.74 mmol) was dissolved in MeOH (25 mL), DMSO (4.4 mL), and TEA (0.22 mL, 1.6 mmol). The solution was cooled to 0° C., and a pre-mixed solution of 30% H2O2 (175 μL, 1.5 mmol) and 4N NaOH (384 μL, 1.5 mmol) was added. The reaction was stirred for 1 hour at 0° C. An additional amount of the pre-mixed solution 30% H2O2 (175 μL, 1.5 mmol) and 4N NaOH (384 μL, 1.5 mmol) was added, and the reaction was stirred for an additional hour at 0° C. MeCN (10 mL) was then added and the solution was stirred for 10 minutes at room temperature. The solvents were removed under reduced pressure, and the residue was subjected to silica flash column chromatography (MeOH/DCM) to give tert-butyl (2R,3R)-1-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (313) (430 mg, 0.74 mmol, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH2:11]C)([CH2:9]C)[CH3:8])[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:15]=[C:16]([F:23])[C:17]([O:21][CH3:22])=[C:18]([OH:20])[CH:19]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:28]=O.C(=O)C1C=CC=CC=1>C(O)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[C:15]3[C:16]([F:23])=[C:17]([O:21][CH3:22])[C:18]([OH:20])=[CH:19][C:14]=3[C:3]3[C:4]([CH3:13])=[N:5][N:6]([C:7]([CH3:9])([CH3:8])[CH3:11])[C:2]=3[N:1]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC(C)(CC)n1nc(C)c(-c2cc(O)c(OC)c(F)c2)c1N
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: O=Cc1ccccc1
Solvent: CC(=O)O
Product: COc1c(O)cc2c(c(-c3ccc(OCc4ccccc4)c(Cl)c3)nc3c2c(C)nn3C(C)(C)C)c1F
Temperature: 90 °C
Reaction time: 7 h
Yield: 44.4 %

Procedure:
5-[5-Amino-1-(1,1-diethylethyl)-3-methyl-1H-pyrazol-4-yl]-3-fluoro-2-(methyloxy)phenol (2.2 g, 7.5 mmol.) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (2.23 g, 8.6 mmol.) were taken into acetic acid (25 mL) and the resulting mixture heated to 90° C. over 12 hours. An additional aliquot of benzaldehyde (250 mg) was then added and heating was continued an additional 7 hours. At this time air was bubbled through the solution at a steady rate while maintaining a temperature of 90° C. then the mixture was allowed to cool to room temperature. The acetic acid was removed and the residue partitioned with saturated aquyeous sodium hydrogencarbonate and ethyl acetate. The organic layer was then washed once with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give a residue containing roughly a 1:1 mixture of two cyclization products. The desired cyclization isomer was purified by silica gel flash chromatography using 2:1 hexanes ethyl acetate as eluent to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6-fluoro-1-methyl-7-(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-8-ol (1.73 g, 44% yield) as a yellow solid after concentration and drying of the pure fractions in vacuo. 1H NMR (400 MHz, CDCl3): 7.66 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.46-7.34 (m, 5H), 7.07 (d, 1H), 6.54 (s, 1H), 5.25 (S, 2H), 4.03 (d, 3H), 2.80 (s, 3H), 1.83 (s, 9H); MS (EI) for C29H27N3O3FCl: 520 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:21](=[O:22])[N:11]2[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][OH:17])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].C(N(CC)CC)C.[S:31]([N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32].[Cl-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.C(O)(=O)C.CCCCCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:21](=[O:22])[N:11]2[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH2:16][O:17][C:45](=[O:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[C:42](=[O:51])[NH:41][S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Reactant: Cc1ccc(S(=O)(=O)N2C(=O)c3ccccc3C2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)c2ccccc2C(=O)OCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]3SC2)cc1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
In N,N-dimethylformamide (8 ml), is dissolved sodium 7β-(t-butoxycarbonyl)amino-3-hydroxymethyl-3-cephem-4-carboxylate (1.60 g), followed by addition of triethylamine (3 ml) and N-tosylphthalimide(1.80 g) under ice-cooling. The mixture is stirred for one hour and then poured into toluene (300 ml). n-Hexane (200 ml) is added and the resultant precipitate is collected by filtration, washed with toluene and dried. The powder thus obtained is dissolved in water (50 ml). The solution is adjusted to pH 3.7 with acetic acid and a saturated aqueous solution of sodium chloride (50 ml) is added. The resultant precipitate is collected by filtration and washed with water. The cake thus obtained is added to a mixed solution of ethyl acetate (30 ml) and water (10 ml). After separation, the ethyl acetate layer is washed with water and water (10 ml) is added. Sodium hydrogen carbonate is added to adjust to pH 6.8. After separation, the aqueous layer is washed with ethyl acetate and ethyl acetate (20 ml) is added. To the mixture, diluted phosphoric acid is added to adjust to pH 4.0. After separation, the ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and concentrated. To the residue, ether is added under stirring and the resultant insolubles are filtered off. The filtrate is concentrated under reduced pressure and carbon tetrachloride is added. The resultant precipitate is collected by filtration and dried phosphorus pentoxide. The procedure provides 7β-(t-butoxycarbonyl)amino-3-[2-(N-tosylcarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (1.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4]>C1COCC1.CCOC(C)=O>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (0.200 g, 1.11 mmol) in THF (6.0 mL) at 0° C. was added borane tetrahydrofuran complex (5.55 mL, 5.55 mmol) slowly. The reaction mixture was slowly warmed to room temperature and stirred at for 3 h. After this time, the reaction mixture was diluted with EtOAc and quenched very slowly with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (0.16 g, 84% yield) as a colorless oil. LCMS, [M+H]+=167.0.