Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:15]=1Cl)[C@H:11]([NH:17][C:18](=[O:51])[C:19]([C:25]1[N:26]=[C:27]([NH:31][C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:28][C:29]=1[Cl:30])=[N:20][O:21][CH2:22][CH2:23][F:24])[C:10]2=[O:52])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C:54]1[S:58][C:57]([S-:59])=[N:56][N:55]=1.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:15]=1[S:59][C:57]1[S:58][C:54]([NH2:53])=[N:55][N:56]=1)[C@H:11]([NH:17][C:18](=[O:51])[C:19]([C:25]1[N:26]=[C:27]([NH:31][C:32]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[S:28][C:29]=1[Cl:30])=[N:20][O:21][CH2:22][CH2:23][F:24])[C:10]2=[O:52])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnc([S-])s1
Reactant: CC(C)(C)OC(=O)C1=C(Cl)CSC2[C@H](NC(=O)C(=NOCCF)c3nc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)sc3Cl)C(=O)N12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NOCCF)c3nc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)sc3Cl)C(=O)N12

Procedure:
A solution of (7R)-3-chloro-7-[2-[5-chloro-2-(tritylamino)-thiazol-4-yl]-2-(2-fluoroethoxyimino)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid t-butyl ester XV (45 mg, 0.057 mmol) and sodium 5-amino-[1,3,4]thiadiazole-2-thiolate (10 mg, 0.064 mmol) in DMF (0.5 mL) was stirred at room temperature for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure the title compound (8 mg, 16%) was isolated by radial chromatography on silica gel (dichloromethane/methanol 50:1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[O:20][CH3:21])[N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)[CH2:3][CH2:4]1)[C:11](=[O:24])[CH:12]=[N:13]2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1cc2ncc(=O)n(CCN3CCC(N)CC3)c2cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1cc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2cc1OC
Yield: 68.6 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-dimethoxyquinoxalin-2 (1H)-one (Intermediate 156, 75 mg, 0.23 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (40 mg, 0.23 mmol), and sodium triacetoxy borohydride (150 mg, 0.69 mmol) were reacted as described according to Example 69 to give 78 mg (68%) of the free base of the product as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[N:19]=[C:18]([O:20][CH2:21][CH2:22][N:23]5C(=O)C6C(=CC=CC=6)C5=O)[CH:17]=[CH:16][N:15]4[C:34]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.O.NN>C(O)C.C(OC(C)C)(C)C>[NH2:23][CH2:22][CH2:21][O:20][C:18]1[CH:17]=[CH:16][N:15]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:2]4([NH2:1])[CH2:5][CH2:4][CH2:3]4)=[CH:7][CH:8]=3)[N:13]=[C:14]2[N:19]=1
Reactant: NC1(c2ccc(-c3nc4nc(OCCN5C(=O)c6ccccc6C5=O)ccn4c3-c3ccccc3)cc2)CCC1
Agent: NN
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CCO
Product: NCCOc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2n1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
2-(2-{2-[4-(1-Amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyrimidin-7-yloxy}-ethyl)-isoindole-1,3-dione (340 mg from Step 1) was dissolved in ethanol (6.8 mL), treated with hydrazine hydrate (98%, 0.045 mL) and heated at 80° C. for 22 h. On cooling, the reaction mixture was diluted with diisopropyl ether and filtered. The filtrate was concentrated in vacuo to give the title compound (225 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13]C=1C(O)=O.CN(C=O)C>C(Cl)Cl>[F:7][C:8]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Oxalyl chloride (0.488 mL, 5.76 mmol) was added to a suspension of 2-fluoro-3-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DCM (10 mL) containing catalytic DMF. The reaction was stirred at room temperature for 90 minutes and solvents were removed in vacuo to afford the desired compound (1.08 g, 99%). The product was used without additional purification.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH:9](Br)Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13]1(=[O:18])[CH2:17][CH2:16][CH:15]=[CH:14]1.[I-].[Na+].Cl.[SH-].[Na+]>CN(C)C=O>[C:13]1(=[O:18])[C:17]2[CH:9]=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]3=[CH:2][C:16]=2[CH2:15][CH2:14]1
Reactant: BrC(Br)c1ccccc1C(Br)Br
Reactant: O=C1C=CCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc3ccccc3cc21
Temperature: 80 °C
Yield: 142.7 %

Procedure:
α,α,α′,α′-Tetrabromo-o-xylene (200 g, 0.48 mole) was dissolved in 2000 mL of dimethylformamide. 2-Cyclopentene-1-one (40 g, 0.25 mole) was added, along with 500 g sodium iodide. The mixture was heated overnight at 80° C. The mixture was cooled and poured into 2 L of ice water containing sodium bisulfide (20 g). The solids were collected and recrystallized from ethanol to give 65 g of benz[f]indan-1-one. The benzindanone was then reduced by dissolving in 600 mL of ethanol and adding 30 g of sodium borohydride, over a 2-hour period. The solution was stirred at room temperature overnight and quenched with 1 N HCl. The ethanol was removed under vacuum, and the product extracted into toluene. The product was then recrystallized from hexanes to give 58 g of benz[f]indan-1-ol. The benzindanol was then dehydrated by refluxing in 100 mL of 10% sulfuric acid overnight. The solution was cooled and extracted with toluene. The product was purified by column chromatography, in hexanes, followed by two recrystallizations from ethanol, and a final recrystallization from hexane to give 10.8 g (13% overall yield) of Benz[f]indene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].I[C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=12
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Ic1cnc2ccccn12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cnc3ccccn23)C1=O
Yield: 19.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 250 mg, 1.4108 mmol) was reacted with 3-iodo-imidazo[1,2-a]pyridine (344 mg, 1.4108 mmol), 1,4-dioxane (10 mL), copper iodide (34 mg), trans-1,2-diamino cyclohexane (68 mg) and potassium phosphate (898 mg, 4.2325 mmol) to afford the crude product. Purification by column chromatography on silica gel (10% MeOH in CHCl3) afforded 82 mg of the product (19.81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:14]=[C:15]([O:18]C)[CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:27].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]2[C:12](=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:27]
Reactant: COc1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1ccc2c(-c3ccccc3Cl)cc(O)cc2n1-c1ccccc1Cl
Reaction time: 4 h
Yield: 94.2 %

Procedure:
1,5-bis(2-chlorophenyl)-7-methoxy-2(1H)-quinolinone (0.863 g, 2.178 mmol) was dissolved in dichloromethane (40 ml) and 1M boron tribromide in dichloromethane (12 ml) added slowly under nitrogen. The solution was stirred at 21° for 4 h, then quenched carefully with methanol (3 ml) and ice (25 g). The mixture was passed through a hydrophobic frit, and the aqueous phase further extracted with dichloromethane (20 ml), and passed through a hydrophobic frit. The dichloromethane extracts were combined and evaporated in vacuo to afford the title compound as a dark solid (0.784 g, 94%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11](N)=[O:12]>>[C:11](=[O:12])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH2:10]
Reactant: CCCCCCCCO
Reactant: NC(N)=O
Product: CCCCCCCCOC(N)=O
Reaction time: 1.5 h

Procedure:
A 1000 mL glass flask equipped with a reflux condenser, a gas-liquid separator, and a stirrer was charged with 522.4 g (4.01 mol) of 1-octanol and 60.07 g (1.00 mol) of urea. While the mixture was stirred at 500 rpm and nitrogen gas was allowed to flow at 30 mL per minute, the mixture was allowed to react at 165° C. After 90 min, 52.1 g (0.87 mol) of urea was added, and after 120 min, 49.34 g (0.82 mol) of urea was added, and the mixture was allowed to react at a reaction temperature of 165° C.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:8]([CH:12]=[C:13](Br)Br)[CH2:9][S:10](=[O:11])[C@H:5]12)=[O:2].C([Li])CCC.Cl>C(OCC)(=O)C>[CH:1]([NH:3][CH:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:8]([C:12]#[CH:13])[CH2:9][S:10](=[O:11])[C@H:5]12)=[O:2]
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Br)Br)CS(=O)[C@H]12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2S(=O)C1
Temperature: -20 °C
Yield: 98.8 %

Procedure:
To a solution of benzhydryl 7-formamido-3-(2,2-dibromovinyl)-3-cephem-4-carboxylate-1-oxide (1.8 g) was added n-butyl lithium (7.27 ml of 1.65M solution in hexane) at -65° to -60° C. under a nitrogen atmosphere. After the resultant mixture was stirred at the same temperature for 30 minutes, ethyl acetate (50 ml) was added to the reaction mixture. The reaction mixture was warmed to -20° C., and hydrolysed with 10% hydrochloric acid. The organic layer was separated and washed with water and brine, dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7-formamido-3-ethynyl-3-cephem-4-carboxylate-1-oxide (1.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:23].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:23]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
tert-Butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) in dichloromethane (20 ml) was stirred under nitrogen. Trifluoroacetic acid (5 ml) was then added dropwise and the reaction was left to stir for 2 hours. 1M sodium hydroxide was added to the reaction until basic, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Product purified by chromatography (5% ethanol/dichloromethane to 10% ethanol/dichloromethane) and solvent removed under reduced pressure to leave an oil which crystallised over the period of 48 hours. The resulting solid was triturated with diethyl ether and filtered to leave 1-(4-chloro-3-fluorobenzyl)-4-piperidinamine (0.500 g) as a white solid.
Reaction SMILES: O.C[O:3][C:4]([C:6]1[C:7]([Cl:28])=[N:8][C:9]2[CH:10]=[C:11]3[O:27][CH2:26][CH2:25][O:24][C:12]3=[CH:13][C:14]=2[C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=O.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[Cl:28][C:7]1[C:6]([CH2:4][OH:3])=[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[C:14]2[CH:13]=[C:12]3[O:24][CH2:25][CH2:26][O:27][C:11]3=[CH:10][C:9]=2[N:8]=1
Reactant: COC(=O)c1c(Cl)nc2cc3c(cc2c1CN1CCN(C)CC1)OCCO3
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2c(CO)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with an overhead mechanical stirrer, a water-cooled condenser and nitrogen flow is maintained. The flask is charged with [7-chloro-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (194 g, 495 mol), prepared as in example 13d, as a solution in 1 L of methylene chloride. To the solution is added 1M diisobutylaluminum hydride in methylene chloride (2.00 L, 2.00 mol) over 15 min. The solution is heated to reflux during the addition. The reaction is allowed to cool to ambient temperature and stirred for 4 h. The reaction mixture is transferred to a 15-L separatory funnel containing a saturated solution of Rochelle's salt (5 L). After being stirred for 2.5 h, the organic layer is separated and the aqueous layer is extracted with methylene chloride (3×2.5 L). The combined organic layers are washed with brine (3 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with methylene chloride (500 mL) and hexane (1 L). The mixture is swirled at 0° C. for 30 min. The precipitate is collected on a Buchner funnel, washed with 1 liter of hexane and dried in vacuo. at 30° C. yielding [7-chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol as a yellow crystalline solid: mp 178°-180° C. 1H NMR (CDCl3, 200 MHz) δ2.26 (s, 3H), 2.63 (br. s, 4H), 4.00 (s, 2H). 4.39(s, 4H), 4.93 (s, 2H), 6.10 (br. s, 1H), 7.46 (s, 1H), 7.51 (s, 1H). Elemental analysis: Calculated for C18H22ClN3O3 : C 59.42, H 6.09, N 11.55. Found: C 59.41, H 6.12, N 11.46.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]/[C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#CC#CC1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Reaction time: 0.58 h
Yield: 55.6 %

Procedure:
To a mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.40 g, 1.2 mmol) and 3-cyclopentylprop-2-ynenitrile (0.30 g, 2.5 mmol) in DMF (8 mL) was added potassium carbonate (0.09 g, 0.6 mmol). The mixture was stirred for 35 min. The reaction was diluted with ethyl acetate and brine, and the aqueous portion extracted with three volumes of ethyl acetate. The combined organic extracts were washed with brine again, then were dried over sodium sulfate, decanted and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (290 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[Li+]>O1CCCC1>[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
An oven-dried, three-necked, 1 L 24/40 round-bottom flask equipped with a mechanical stirrer, a septum and a nitrogen inlet was charged with a solution of 20.00 g (0.110 mol) of 4-chlorocinnamic acid in 400 mL of anhydrous tetrahydrofuran. The reaction mixture was purged with nitrogen and stirred at −20° C. and then 19.93 mL (0.143 mol) of triethylamine and 14.84 mL (0.120 mol) of pivaloyl chloride were added via syringe. The reaction mixture was stirred at −20° C. for 30 min, then at room temperature for 1.5 h. A separate, oven-dried, three-necked, 2 L 24/40 round-bottom flask was equipped with a mechanical stirrer, and a nitrogen inlet. The contents were purged with nitrogen gas and then charged with 16.243 g (0.092 mol) of (S)-(−)-4-benzyl-2-oxazolidinone, 4.274 g (0.101 mol) of finely powdered anhydrous lithium chloride, 400 mL of anhydrous tetrahydrofuran and 16.61 mL (0.119 mol) of triethylamine. The reaction flask was fitted with an oven-dried fritted vacuum filtration funnel in one of its necks, and the reaction mixture was stirred at −20° C. The mixed anhydride prepared in the first reaction flask was separated from precipitated triethylamine hydrochloride by rapid filtration into the second flask with the aid of a slight vacuum applied to the filtration funnel. The reaction mixture in the second flask was again purged with nitrogen, stirred for 30 min at −20° C., then allowed to warm to room temperature and stirred an additional 5 h. At this point the reaction mixture was filtered again and concentrated in vacuo. The crystalline residue was dissolved in methylene chloride, washed with 0.5 M hydrochloric acid, water, saturated aqueous sodium bicarbonate, brine, then dried (MgSO4), filtered and evaporated. The residue was purified by rapid filtration through a six inch bed of silica gel 60 eluted with methylene chloride. Evaporation of the purified fractions and drying in vacuo afforded 23.38 g of the title compound.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]([CH3:35])[C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:30]3[N:29]=[C:28]([CH3:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=1)(O)=O.C1(P([N:50]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[NH2:50][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]([CH3:35])[C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:30]3[N:29]=[C:28]([CH3:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2C(=O)O)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2N)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Temperature: 80 °C
Yield: 85.2 %

Procedure:
A mixture of N-(2-carboxy-4-methylphenyl)-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylamino-benzamide (350 mg), diphenylphosphorylazide (224 mg) and triethylamine (82.5 mg) in dioxane (10 mg) was heated at 80° C. for 6 hours. After evaporation, the residual oil was subjected to silica gel column and the column was eluted with 5% methanol in chloroform. Object fractions were collected and evaporated in vacuo and the residue was solidified from chloroform to give N-(2-amino-4-methylphenyl)-3-methoxy-N-methyl-4-(2-methyl-1-H-benzimidazol-4-yl)carbonylamino-benzamide (280 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]([CH3:46])([CH3:45])[C:38]([O:40]C(C)(C)C)=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:21](=[O:22])[C@H:20]([CH3:23])[O:19][C:18]3[N:24]=[CH:25][C:26]([F:28])=[CH:27][C:17]2=3)[CH2:12][CH2:11]1)=[O:9]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]([CH3:45])([CH3:46])[C:38]([OH:40])=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:21](=[O:22])[C@H:20]([CH3:23])[O:19][C:18]3[N:24]=[CH:25][C:26]([F:28])=[CH:27][C:17]2=3)[CH2:12][CH2:11]1)=[O:9]
Reactant: C[C@@H]1Oc2ncc(F)cc2N(C2CCN(C(=O)c3ccc(-c4ccccc4OCC(C)(C)C(=O)OC(C)(C)C)cc3F)CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ncc(F)cc2N(C2CCN(C(=O)c3ccc(-c4ccccc4OCC(C)(C)C(=O)O)cc3F)CC2)C1=O
Yield: 77.9 %

Procedure:
A trifluoroacetic acid solution (10 ml) of tert-butyl 3-{[3′-fluoro-4′-({4-[(3S)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl]piperidin-1-yl}carbonyl)biphenyl-2-yl]oxy}-2,2-dimethylpropanoate (940 mg) was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the resulting residue was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then a 10% aqueous citric acid solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate-hexane was added to the residue to collect the precipitate by filtration. This was redissolved in ethanol, to which water was added, and the resulting precipitate was collected by filtration to afford 3-{[3′-fluoro-4′-({4-[(3S)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl]piperidin-1-yl}carbonyl)biphenyl-2-yl]oxy}-2,2-dimethylpropanoic acid (668 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]3[C:18]=2[CH2:19][N:20]([CH3:27])[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:5][CH:4]=1>C(O)(=O)C.Cl.C(O)(C)C.[Rh]>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][N:12]3[C:18]=2[CH2:19][N:20]([CH3:27])[C:21](=[O:26])[CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:5][CH:4]=1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)c(CN(C)C(=O)CC(C)C)n2c1
Agent: [Rh]
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)CC(=O)N(C)Cc1c(-c2ccc(Cl)cc2)nc2n1CC(C)CC2
Yield: 93.3 %

Procedure:
3 g (8.1 mmol) of N-[{2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl}methyl]-N,3-dimethylbutanamide hydrochloride is dissolved in 200 ml of acetic acid, 0.7 g of rhodium on alumina (5% rhodium) is added and the mixture is hydrogenated under a pressure of approximately 0.35 MPa (50 PSI) until absorption is complete. The catalyst is removed by filtration and the solvent evaporated off under reduced pressure. The residue is taken up with dichloromethane and the solution washed with bicarbonate water. The organic phase is separated after settling and dried over magnesium sulphate. After filtration and evaporation of the solvent, a solid residue is taken up with ether and purified by chromatography on a silica column. The hydrochloride is prepared therefrom in 0.1N hydrogen chloride in isopropyl alcohol. 1.55 g of the expected product is obtained.