Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[CH3:24][C:23]1[N:19]([CH2:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)[CH2:12][CH2:13]2)=[O:29])[N:20]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A stirred solution of ethyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate (13.0 g, 30.2 mmol) (i.e. the product of Example 2, Step B) in methanol (60 mL) was cooled to 0° C. and treated with an aqueous sodium hydroxide solution (1 N, 36.3 mL, 36.3 mmol). The stirred reaction mixture was allowed to warm to room temperature for 5 h. The reaction mixture was cooled again to 0° C. and treated with aqueous hydrochloric acid (1 N, 36.3 mL, 36.3 mmol). The resulting precipitate was collected under filtration, washed with water and dried in a vacuum oven at 100° C. to give 10.95 g of the title compound as a white solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:19]=3)[N:14]=2)[CH:12]=1)=[O:7])C>C1COCC1>[C:25]([NH:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([N:11]1[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1)[NH:22][C:21]2=[O:23])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3ccc(NC(=O)c4ccccc4)cc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
Aqueous 1M KOH (1.06 mL, 1.06 mmol) was added to 1-(6-benzoylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.142 g, 0.343 mmol) in THF (1.0 mL). The reaction mixture was allowed to stir at room temperature for 18 h and was then concentrated. The residue was redissolved in water (5 mL) and brought to pH 1 with aqueous 1M HCl (3 mL). The resulting precipitate was collected by filtration to yield the titled compound (0.110 g, 82% yield). MS (ESI/Cl): mass calcd. for C19H13N5O4, 375.1; m/z found, 376.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.99 (s, 1H), 12.79 (s, 1H), 10.60 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.26 (s, 1H), 8.23 (dd, J=8.8, 2.4 Hz, 1H), 8.04-7.99 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.65-7.60 (m, 1H), 7.59-7.54 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (300 mg, 0.98 mmol), tetrahydrofuran (15 mL) and lithium hydroxide (70 mg, 2.94 mmol). The reaction mixture was stirred at 50° C. overnight, and then filtered through sodium sulfate. The filtrate was concentrated under reduced pressure to afford the product as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
5-Benzyloxy-4-tert-butyl-2-formylbenzofuran (700 mg, 2.3 mmol) was dissolved in acetic acid (30 ml) and, after addition of 10% Pd on carbon (700 mg), the solution was stirred under a hydrogen atmosphere (5 arm.) for 8 h. After filtering off the Pd on carbon, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was subjected to silica gel chromatography and eluted with a solvent system consisting of a 4:1 mixture of hexane and ethyl acetate to afford 4-tert-butyl-5-hydroxy-2-methylbenzofuran [320 mg (yield, 68%)] as a pale yellow, fine-grained crystal.
Reaction SMILES: C1COCC1.[NH:6]1[C:10]2[CH:11]=[C:12]([C:15](=O)[CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH3:18][C:19]([S@:22]([NH-:24])=[O:23])([CH3:21])[CH3:20].[BH4-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CCO.O>[NH:6]1[C:10]2[CH:11]=[C:12]([C@H:15]([NH:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: CC(=O)c1ccc2nn[nH]c2c1
Reactant: CC(C)(C)[S@]([NH-])=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc2nn[nH]c2c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a THF (25 ml) solution of 1-(1H-1,2,3-benzotriazol-6-yl)ethanone (1.85 g, 11.5 mmol), (R)-(+)-2-methyl-2-propanesulfinylamide (2.30 g, 18.9 mmol) and titanium(IV) ethoxide (25 ml) were added and the mixture was stirred for 24 hours at 70° C. Then, the mixture was cooled to 0° C. and sodium borohydride (1.5 mg, 40 mmol) was added. After stirring for 2 hours, water and EtOH were added to the mixture with stirring for 1 hour at room temperature. Filtration, evaporation gave N-[(1R)-1-(1H-1,2,3-benzotriazol-6-yl)ethyl]-2-methylpropane-2-sulfinamide (MS (ESI) m/z 265 (M−H)−, 267 (M+H)+) which was treated with hydrochloric acid-MeOH (2.0 M, 15.0 ml) and 1,4-dioxane (15.0 ml) for 1.5 hours at room temperature. Then, the reaction mixture was evaporated and diethyl ether was added to form a precipitate, which was collected, washed with diethyl ether to give (1R)-1-(1H-1,2,3-benzotriazol-5-yl)ethanamine hydrochloride (1.26 g, 68%) MS (ESI) m/z 161 (M−H)−
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[C:10]3[C:15]([N:16]=[CH:17][C:8]2=[N:7][N:6]=1)=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[CH:11]=3)[CH2:2][CH2:3][CH3:4].[OH:20]O>CC(O)=O>[CH2:1]([C:5]1[N:9]2[C:10]3[C:15]([NH:16][C:17](=[O:20])[C:8]2=[N:7][N:6]=1)=[CH:14][C:13]([Cl:18])=[C:12]([Cl:19])[CH:11]=3)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1nnc2cnc3cc(Cl)c(Cl)cc3n12
Solvent: CC(=O)O
Product: CCCCc1nnc2c(=O)[nH]c3cc(Cl)c(Cl)cc3n12
Temperature: 60 °C

Procedure:
The carbonyl compound was prepared by combining 500 mg (1.7 mmol) of the quinoxaline compound (7) and 16 nil HOAc, and then adding 5 ml of 30% H2O2. The mixture was heated to 60° C. for 16 hours, and then cooled. The product was recovered by filtration and dried at 0.5 mm and 60° C. overnight, yielding 150 mg of 1-n-butyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (8).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Cl.[C:29](=[NH:34])(OCC)[CH3:30].C(N(CC)CC)C>ClCCl>[C:29]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)(=[NH:34])[CH3:30]
Reactant: CCOC(C)=N
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.01 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.9 μmol), ethyl acetimidate hydrochloride (12.1 mg, 98.2 μmol) and triethylamine (22.8 μL, 164 μmol) in dichloromethane was stirred at room temperature overnight. The mixture was concentrated and the crude product was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 7.01% yield. LCMS m/z (%)=408 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.2 (s, 2H) 2.7 (s, 3H) 3.0 (s, 1H) 3.6 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.2 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.2 (dd, J=7.3, 2.8 Hz, 1H) 7.2 (d, J=8.6 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=3.0 Hz, 1H) 7.8 (dd, J=9.1, 2.5 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:14]([N:18]1[C:22](=[O:23])[C:21](Cl)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[S:19]1(=[O:33])=[O:32])[CH2:15][CH2:16][CH3:17]>CN(C=O)C>[CH2:14]([N:18]1[C:22](=[O:23])[C:21]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=2)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[S:19]1(=[O:32])=[O:33])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN1C(=O)C(Cl)=C(c2cccc(Cl)c2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2cccc(Cl)c2)S1(=O)=O
Temperature: 140 °C
Yield: 184.9 %

Procedure:
4-Morpholin-4-ylaniline (53 mg, 0.30 mmol) was added to a solution of 2-butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (50 mg, 0.15 mmol) in dry DMF (1.0 mL) at rt and under an atmosphere of nitrogen. The reaction mixture was heated in a microwave reactor at 140° C. for 25 mins, whereafter the solvents were removed. Another portion of 4-morpholin-4-ylaniline (160 mg, 0.90 mmol) was added to a solution of 2-butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.45 mmol) in dry DMF (2.0 mL) at rt and under an atmosphere of nitrogen. The reaction mixture was heated in a microwave reactor at 140° C. for 25 mins, whereafter the solvents were removed. The obtained two mixtures were combined and purified using preparative HPLC (column ACE C8, 0.1M NH4OAc/MeCN, gradient) followed by column chromatography (Horizons Biotage, Heptane:EtOAc, 3:1, isocratic run) to give the title compound (132 mg, 62%) as a yellow solid; 1H NMR (500 MHz, CDCl3): δ 7.22 (bs, 1H), 7.13-7.19 (m, 2H), 7.06-7.11 (m, 1H), 6.93-6.96 (m, 1H), 6.65-6.69 (m, 2H), 6.55-6.60 (m, 2H), 3.82-3.86 (m, 4H), 3.75-3.80 (t, 2H), 3.04-3.08 (m, 4H), 1.83-1.91 (m, 2H), 1.44-1.52 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.3, 149.8, 134.2, 132.6, 130.3, 129.3, 129.0, 127.9, 127.3, 126.8, 124.3, 115.6, 107.8, 66.9, 49.6, 40.5, 30.4, 20.3, 13.8; Mass Spectrum: M−H 474.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:20]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C(#N)C>[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCc1ccccc1
Agent: [Pt]
Solvent: CC#N
Product: Nc1cnc2cc(Br)ccc2c1NCc1ccccc1
Yield: 63.4 %

Procedure:
Platinum on carbon (1.2 g of 5%) was added to a solution of N-benzyl-7-bromo-3-nitroquinolin-4-amine (10.9 g, 30.4 mmol) in acetonitrile (300 mL) in a Parr vessel. The mixture was placed under hydrogen pressure (30 psi, 2.1×105 Pa) overnight and then filtered through a layer of CELITE filter agent. The filter cake was washed with methanol. The filtrate was concentrated under reduced pressure and further dried for two hours on a vacuum pump to provide 6.33 g of N4-benzyl-7-bromoquinoline-3,4-diamine as a dark green solid.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]([CH3:16])([CH3:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)O.FC(F)(F)S([O-])(=O)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:15][C:5]1([CH3:16])[CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[C:3]=2[O:4]1
Reactant: Cc1ccc(C(O)C(C)(C)Oc2cccc(C)c2C)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3ccc(C)c(C)c3OC2(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 2-(2,3-dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-ol synthesized in Reference Example 135 (17.0 g, 60 mmol) in toluene (200 mL) was added trifluoromethanesulfonate (0.53 mL, 6 mmol) at 0° C., and the mixture was warmed to 50° C. The mixture was stirred at the same temperature for 30 minutes and was reacted under reflux condition for 2 hours. The reaction solution was cooled to 0° C., and then was poured into a saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with a saturated brine, and dried over sodium sulfate, and the solvent then was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 9.3 g (yield 58%) of the title compound as an oily matter.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:43]=[CH:42][C:20]([C:21]([N:23]([CH3:41])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][C:37]([O:39][CH3:40])=[O:38])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:43]=[CH:42][C:20]([C:21]([N:23]([CH3:41])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C=CCCCCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(6-methoxycarbonyl-5-hexenyloxy)phenyl]benzamide (360 mg) and nickel chloride hexahydrate (594 mg) in methanol (15 ml) and tetrahydrofuran (15 ml) was treated at 0° C. with sodium borohydride (283 mg) and stirred at 0° C. for 4 hours. The reaction mixture was diluted with tetrahydrofuran and filtered through a bed of Celite and then concentrated. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, concentrated to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(6-methoxycarbonylhexyloxy)phenyl]benzamide (340 mg).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:55])=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[C@@H:40]([CH3:54])[CH2:39]3)[CH:32]=2)[CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[F:55][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:17]([C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=2)=[O:19])=[CH:30][C:29]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[C@@H:40]([CH3:54])[CH2:39]2)[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C5CCNCC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of the commercially available 3-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)benzoic acid (183 mg, 0.60 mmol) in 2 mL of dry DMF was added phenylmethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (250 mg, 0.60 mmol), DIPEA (0.2 ml, 1.4 mmol), and HATU (251 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 2 h before addition of 2 mL of saturated Na2CO3 and 10 mL of EtOAc. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was mixed with 4M HCl in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (162 mg, 43%). LC/MS: m/z, 635 (M+H), 1.75 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 155.4 %

Procedure:
To a solution of 5-nitropicolinic acid (CIII) (500 mg, 2.97 mmol) in DMF (15 mL) was added pyrrolidine (244 μl, 2.47 mmol) and DIPEA (1.03 mL, 5.95 mmol). The reaction was cooled at 0° C. before adding HATU (1.13 g, 2.47 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was concentrated under vacuum and then dissolved in a mixture of water and 10% iPrOH/CHCl3. The organic layer was separated and the aqueous phase was washed again with 10% iPrOH/CHCl3. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to yield (5-nitropyridin-2-yl)(pyrrolidin-1-yl)methanone (CIV) as a red solid (849 mg). ESIMS found for C10H11N3O3 m/z 222.1 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:11]1([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:15]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1

Procedure:
A suspension of 2.9 g (7.76 mmol) ethyl 4-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-butanoate and 300 mg 10% Pd/C in 60 mL MeOH was hydrogenated at RT and 50 psi hydrogen pressure for 24 h. The catalyst was filtered off, the mixture was evaporated down i.vac., the residue was taken up in a little DIPE and isopropanol and combined with 4 M HCl in 1,4-dioxane. The precipitated bis-hydrochloride salt was separated off and dried.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH2:10]([OH:14])[CH2:11]CC>>[CH:11]1([NH:1][C:2]([NH2:4])=[O:3])[NH:4][C:2](=[O:3])[NH:1][C:10]1=[O:14]
Reactant: NC(N)=O
Reactant: CCCCO
Agent: O=S(=O)(O)O
Product: NC(=O)NC1NC(=O)NC1=O
Temperature: 85 °C

Procedure:
A mixture of 30.6 g of glyoxylic acid butyl ester butyl hemiacetal (0.15 mol), 30.0 g of urea (0.5 mol), 300 g of n-butanol and 7.5 g of 8% strength butanolic sulfuric acid was heated at 85° C. for a total of 4 hours. After the reaction had ended, the suspension formed was cooled to room temperature, whereupon a colorless precipitate separated out, which was filtered off, washed with methanol and dried in vacuo at 75° C. 23.1 g, that is to say 66% of theory, of crystalline allantoin acid butyl ester were obtained by this reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]([CH3:21])[CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]([CH3:21])[CH2:8][CH:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[OH:10]
Reactant: COc1cccc(CN(C)CC(=O)c2ccc3ccccc3c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CN(C)CC(O)c2ccc3ccccc3c2)c1
Temperature: 12.5 °C
Reaction time: 0.83 h

Procedure:
A solution of the ketone, Compound 4, (512.2 g, 1.57 mol) in methanol (4.0 L) was split equally into two flasks. To each half of the ice-cold solution was added sodium borohydride (33.0 g, 0.87 mol) in batches (˜30 min). After the addition, the reaction solution was stirred at 0° C. (internal temperature 10-15° C.) for 50 min before it was quenched slowly with water (˜500 mL). The reaction mixture was then concentrated in vacuo to remove most of the organic solvent. The residue obtained from the two batches were combined, extracted with dichloromethane (2×), dried over sodium sulfate and concentrated in vacuo. The alcohol, Compound 5, was obtained as a yellow oil (510.4 g, quantitative), and was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ 7.84-7.80 (m, 4H), 7.47-7.44 (m, 3H), 7.27-7.24 (m, 1H), 6.92-6.83 (m, 3H), 4.92 (dd, J=10.0, 4.0 Hz, 1H), 4.14 (br s, 1H), 3.81 (s, 3H), 3.74 (d, J=13.0 Hz, 1H), 3.53 (d, J=13.0 Hz, 1H), 2.68-2.60 (m, 2H), 2.36 (s, 3H); ESI MS m/z 322 [M+H]+.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.CO.O>[NH2:10][C@@H:11]1[C:30](=[O:31])[N:13]2[C:14]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[C:15]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[CH2:16][S:17][C@H:12]12
Reactant: CC(C)(C)OC(=O)C1=C(C2CCOC2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)C1=C(C2CCOC2)CS[C@@H]2[C@H](N)C(=O)N12

Procedure:
t-Butyl (6R,7R)-7-phenylacetamido-3-[(RS)-tetrahydrofuran-3-yl]ceph-3-em-4-carboxylate (0.9 g) in dichloromethane (15 ml) with N-methylmorpholine (0.45 g, 0.49 ml) was successively treated with phosphorus pentachloride (0.549 g) in dichloromethane (13.74 ml), methanol (10 ml) and water (10 ml) as described in Example 2(f). After purification by flash chromatography on silica gel eluting with 60, 80% ethyl acetate/hexane and then ethyl acetate, the title compound was obtained as a yellow solid (0.481 g, 73%); (Found: M+, 326.1304. C15H22N2O4S requires M, 326.1300); νmax (CH2Cl2) 3408, 1775 and 1716 cm-1 ; δH (CDCl3) 1.55 (9 H, s), 1.69-2.41 (3 H, m's), 3.31 and 3.48 with 3.34 and 3.49 (2 H, 2ABq's, J 17.5 and 17.5 Hz), 3.69-3.83 (4 H, 2 s's overlapping m), 3.97-4.05 (2 H, m), 4.72 and 4.74 (1 H, 2 d's, J 4.3 and 4.4 Hz) and 4.95 and 4.97 (1 H, 2 d's, J 4.3 and 4.4 Hz).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[NH2:30])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]=[C:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]1[CH2:42][C:43](O)=[O:44]>>[O:31]=[C:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]1[CH2:42][C:43]([NH:30][C:29]1[CH:28]=[CH:27][S:26][C:25]=1[C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:24]=1)=[O:44]
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: Nc1ccsc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(CN1C(=O)CCc2ccccc21)Nc1ccsc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
The title compound was prepared from 2-(1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid using protocol B (269 mg, 32%). Method [7] Retention time 9.32 min by HPLC (MH+ 595).