Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (5.5 g, 56.4 mmol) was added to a suspension of 4-iodobenzoyl chloride (10.0 g, 37.5 mmol) and toluene (60 mL) at 0° C. After 10 min, a solution of sodium carbonate (16.0 g, 151 mmol) and water (250 mL) was added over 50 min via addition funnel. With vigorous stirring, the reaction was maintained at 0° C. for 2 h and then partitioned. The toluene layer was washed with water (125 mL), washed with brine (125 mL), and then concentrated. The residue was redissolved in toluene and filtered to remove trace solids. This solution was concentrated to give 10.5 g of 4-iodo-N-methoxy-N-methylbenzamide as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.32 (d, 2H), 3.53 (s, 3H), 3.25 (s, 3H); LCMS: 292.4 (M+H)+. Step 2: 1-(4-Iodophenyl)-2-(4-methoxyphenyl)ethanone
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[N:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:14]2[CH2:15][CH2:16][N:12]([CH:11]=[N:10][C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)[C:13]2=[N:17][N+:18]([O-:20])=[O:19])=[CH:24][N:23]=1
Reactant: CC(=O)c1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A mixture of 3.00 g of 1-(4-acetylphenyliminomethyl)-2-nitroiminoimidazolidine, 2.12 g of 2-chloro-5-chloromethylpyridine, 3.01 g of potassium carbonate, and 7 ml of DMSO was agitated at 60° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated to obtain an oily residue. To the resultant oily residue was added ethyl acetate, followed by separation of the resultant crystals by filtration and drying to give 1.73 g of 1-(2-chloropyridine-5-ylmethyl)-2-nitroimino-3-(4-acetylphenyliminomethyl)imidazolidine.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:35]([CH2:6][CH2:7][C:8]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[N+:36]=[N-:37]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 70 °C
Yield: 49 %

Procedure:
To a solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 0.47 mmol) in anhydrous DMF (5 mL) was added NaN3 (92 mg, 1.42 mmol). The reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (30 mL), and water (20 ml). The organic phase was washed with water (3×20 mL), dried over Na2SO4 and evaporated to give 6-(2-azidoethyl)-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 49%).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].F[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:22][C:3]1([NH:2][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:19])[CH3:20]
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ccc(C(F)(F)F)cn1

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 1.50 g, 4.51 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (CAS number 69045-82-5; 0.652 mL, 5.41 mmol) and DIPEA (2.36 ml, 13.5 mmol) in DMSO (10 ml) was subjected to microwave irradiation at 140° C. for 4 hours. The reaction was diluted with ethyl acetate (200 ml) and a saturated solution of sodium bicarbonate (100 ml). The aqueous layer was further extracted with ethyl acetate (100 ml). The combined organics were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-20% diethyl ether/petrol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH:8]=[C:9]([F:11])[F:10])[CH2:5][C:4]1=[O:12].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=[C:20]2[N:19]=1>O1CCOCC1>[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[C:26]([CH2:2][N:3]3[CH2:7][CH:6]([CH:8]=[C:9]([F:11])[F:10])[CH2:5][C:4]3=[O:12])=[C:20]2[N:19]=1
Reactant: O=C1CC(C=C(F)F)CN1CCl
Reactant: Clc1ccn2nc(C3CC3)cc2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nn2ccc(Cl)nc12
Yield: 69 %

Procedure:
To a solution of 1-(chloromethyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one x276 (2.55 mmol, 2 eq, 500 mg) in 15 ml of dioxane at 0° C. are added successively AlCl3 (5.1 mmol, 2 eq, 680 mg) and 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274 (2.55 mmol, 1 eq, 495 mg). The mixture is stirred at reflux for 1 hour, then quenched with an aqueous saturated NH4Cl solution and the resulting mixture extracted with AcOEt. The cumulated organic layers are washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 98/2/0.2), followed by a crystallization step in hexane. 1-[(5-chloro-2-cyclopropyl pyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 219 is obtained as a solid (623 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12

Procedure:
A solution of methyl 6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate (24 mg, 0.056 mmol) in methanol (0.5 mL) and 1 M sodium hydroxide (0.17 mL, 0.17 mmol) was heated at 75° C. for 24 hours. The reaction was acidified with 1 M HCl to pH=2 then diluted with ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using reverse-phase chromatography to give the title compound as the formic acid salt. MS (ES+) 415.129 (M+H)+ Retention time: 2.2 min; Waters Atlantis dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA) Flow: 2.0 mL/min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13].[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21].CO>O1CCCC1>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13])=[O:24])[CH3:27]
Reactant: CC(=C1C(=O)Nc2ccc(N)cc21)c1ccc[nH]1
Reactant: CCOC(=O)CN=C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Reaction time: 8 h

Procedure:
A solution of 5-amino-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (360 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was treated with ethyl isocyanatoacetate (195 mg, 1.5 mmol) at ambient temperature. After stirring overnight, methanol (5 mL) was added and the reaction was concentrated. Chromatography on SiO2 (7.2 g) using 1:2 hexane/ethyl acetate afforded 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H), 2.82 (s, 3H), 3.96 (d, 2H), 4.22 (q, 2H), 6.44 (m, 2H), 6.88 (d, 1H), 7.16 (m, 1H), 7.28 (d, 1H), 7.40 (m, 1H), 7.96 (m, 1H), 8.76 (s, 1H), 11.02 (s, 1H) ppm; (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH:12](OCC)(OCC)OCC>>[Cl:1][C:2]1[N:3]=[C:4]([S:10][CH3:11])[N:5]2[CH:12]=[N:9][N:8]=[C:6]2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc(Cl)cc(NN)n1
Product: CSc1nc(Cl)cc2nncn12

Procedure:
A mixture of 7.0 g (0.037 mole) of 4-chloro-6-hydrazino-2-methylthiopyrimidine and 100 ml of triethyl orthoformate was heated at reflux for 48 hours. Cooling provided a precipitate which was isolated by filtration, and then recrystallized from an ethanol-heptane mixture, with treatment with decolorizing charcoal. The product was red crystals of 7-chloro-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 164°-165° C.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](Cl)(=O)[CH3:7].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>C(#N)C.[Cu]>[N:10]1([CH:1]([O:5][CH2:6][CH3:7])[CH:2]([CH3:4])[CH3:3])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: CC(C)C=O
Reactant: CC(=O)Cl
Agent: [Cu]
Solvent: CC#N
Product: CCOC(C(C)C)n1cncn1

Procedure:
The diethylacetal of iso-butyraldehyde (2.8 g) was reacted with acetyl chloride (2.7 g) in the presence of copper bronze; the product was reacted with 1,2,4-triazole (3.0 g) in acetonitrile (50 ml) to give the title compound as a viscous oil which GLC showed to be slightly impure.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[CH3:13][C:14]#[N:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:13][C:14]#[N:15])=[CH:11][CH:12]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(F)cc1
Product: N#CCC(=O)c1ccc(F)cc1
Yield: 86 %

Procedure:
Using general method L, ethyl 4-fluorobenzoate (119 g, 0.71 mol) and MeCN (75 mL) were combined to afford 3-(4-fluorophenyl)-3-oxopropionitrile (100 g, 86% yield). 1H NMR (300 MHz, CDCl3): δ 7.98-7.94 (m, 2H), 7.22 (d, J=6.6 Hz, 2H), 4.07 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=1)[CH:5]=2.[C:17]1([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CS(O)(=O)=O.S[CH2:36][CH2:37][C:38]([OH:40])=O>CO>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([C:2]3[CH:3]=[CH:4][C:12]([O:40][C:38]4[CH:37]=[CH:36][CH:7]=[CH:6][CH:5]=4)=[CH:13][CH:14]=3)([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:29][CH:28]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)CCS
Reactant: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: Brc1ccc2c(c1)C(c1ccc(Oc3ccccc3)cc1)(c1ccc(Oc3ccccc3)cc1)c1cc(Br)ccc1-2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 2,7-dibromofluorenone (26 g, 77 mmoles) and phenyl ether (170 g, 1 mole) is added 60 mL of methanesulfonic acid and 0.5 mL of 3-mercaptopropionic acid. The mixture is heated and stirred at 60° C. for 30 minutes, and then at 25° C. for 16 hours. The mixture is again stirred at 60° C. for 30 minutes and then at 25° C. for 3 hours. The mixture is poured into 1.4 L of ice water and 200 mL of methanol and allowed to stand in the hood for 4 days. The semi-solid precipitate is separated by decanting the supernatant liquid and then digesting with 1:1 v/v acetonitrile-hexane. The title compound is obtained as a colorless powder (32 g, 64 percent), melting point 178° C. to 180° C. HPLC analysis shows a purity of greater than 99 percent and the PMR spectrum (DMSO-d6) is consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[H][H]>C(Cl)Cl.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([O:11][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7.0 g (0.045 mol) of 3-fluoro-4-nitrophenol and 6.7 g (0.067 mol) of triethylamine in 20 ml of methylene chloride cooled to 0° is added 6.5 g (0.054 mol) of pivaloyl chloride in a dropwise manner. The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over magnesium sulfate. Filtration and removal of the solvents gives crude 2-fluoro-4-pivaloyloxy-nitrobenzene which is dissolved in 200 ml of absolute ethanol. To the solution is added 0.9 g of 5% palladium on carbon, and the mixture is then hydrogenated under 30 psi hydrogen for two hours. The catalyst is filtered and the solvent removed to give 2-fluoro-4-pivaloyloxyaniline.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(C12CC3CC(CC(C3)C1)C2)=O>C1COCC1>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 221.8 %

Procedure:
Using the procedure described in Example 5 and Example 17, L-homoproline-L-isoleucine benzylamide (75 mg, 0.22 mmol), was treated with triethylamine (0.15 mL, 1.12 mmol, 5 eq), 1-adamantyl bromomethyl ketone (92 mg, 0.36 mmol, 1.6 eq), and THF (10 mL), to provide 64 mg (56%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-homoproline] benzylamide.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH2:35][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][NH:23][CH3:22])=[CH:26][CH:27]=3)[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CNCc1ccc(C2CCNC2)cc1
Product: CNCc1ccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)cc1
Yield: 51 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.89 g, 3.0 mmol) and N-methyl-4-(3-pyrrolidinyl) benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.71 g, 51%) as a yellow solid, mp 201°-205° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:26][C:27]1[CH:32]=[C:31]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:15]([NH:14][C@H:5]2[CH2:4][O:3][C:2]([CH3:25])([CH3:1])[O:7][C@H:6]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
Reactant: OB(O)c1cccc(Cl)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: COCCOC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccc(Cl)c2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
To a reaction flask charged with 16.2 mg (0.014 mmol) of Tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (2.0 mL) under nitrogen was added 142 mg (0.31 mmol) of the product from Example 6 and ethylene glycol dimethyl ether (0.8 mL). The resulting yellow solution was stirred for 10 min before the addition of 57.8 mg (0.37 mmol) of 3-chlorophenylboronic acid dissolved in ethylene glycol dimethyl ether (0.6 mL) and the subsequent addition of 0.32 mL (0.65 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for ˜24 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the residue was purified by column chromatography (hexane/ethyl acetate) to yield 80 mg (59%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:15]2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38].N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:27])[CH:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:15]2)=[CH:11][CH:12]=1)[C:4]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[O:5]
Reactant: CC(C)C(C(=O)O)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Reactant: COC(=O)/C=C/c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccccc1NC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(C)C

Procedure:
A solution of 50 mg (0.14 mmol) of 3-methyl 2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoic acid (enantiomer 2; Example 79A), 20 mg (0.11 mmol) of methyl (2E)-3-(2-aminophenyl)prop-2-enoate, 1.5 ml of pyridine and 65 mg (0.17 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) in 5 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and after filtration the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC. This gave 7 mg (0.01 mmol, 9.8% of theory) of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].O1CCC[CH2:22]1>O.CO.C(OCC)(=O)C>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:22])=[O:6])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)CCCNC(=O)OCc1ccccc1

Procedure:
4-Aminobutyric acid (7.5 g) was dissolved in a mixture of tetrahydrofuran (80 ml) and water (80 ml), which was cooled at 0° to 5° C. in an ice bath. To a resulting mixture was added dropwise benzyloxycarbonyl chloride (10.4 ml) with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0° to 5° C. The reaction mixture was washed with ethyl acetate (300 ml) and aqueous layer was separated, which was adjusted to pH 1.0 with 6N-aqueous hydrochloric acid and extracted with ethyl acetate (300 ml). Organic layer was separated, washed with brine (100 ml×2) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was dissolved in methanol (200 ml) and added conc. sulfic acid (1 ml). The resulting solution was refluxed for 3 hours. Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (300 ml), washed in turn with water (100 ml), saturated sodium hydrogen carbonate in water (100 ml×3) and brine (100 ml×2), and dried over magnesium sulfate. Solvent was removed under reduced pressure to give methyl 4-(benzyloxycarbonylamino)butyrate (14.65 g).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].S(C)C.CO>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:4]([CH2:5][OH:6])[C:3]=1[OH:12]
Reactant: O=C(O)c1ccc(F)c(F)c1O
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1ccc(F)c(F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 3,4-difluoro-2-hydroxy benzoic acid (3.2 g 18.39 mmol) in THF (20 mL) was added BH3.Me2S (7 mL 73.56 mmol) drop wise, over a period of 20 min. at RT. The reaction mixture was stirred at RT for 3 h and monitored by TLC. Methanol (20 mL) was added and the solvent was removed under vacuum. The crude compound was purified by column chromatography over silica gel using a mixture of ethyl acetate and hexane (20:80) as eluent to give the alcohol (2.7 g, 91% yield) MS: m/z 159 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1>COC(OC)N(C)C>[CH3:13][N:14]([CH3:15])[CH:10]=[CH:17][C:16]([C:15]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18]
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Agent: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12

Procedure:
A solution of 1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone (0.0374 g, 0.000153 mol) in N,N-dimethylformamide dimethyl acetal (3.0 ml) was heated to 100° C. for 24 hrs. HPLC showed complete consumption of the starting material. The volatiles were removed in vacuo, yielding a brown solid (0.046 g, quantitative). M.p.=187-189° C.; 300 MHz 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.72-7.64 (m, 3H), 7.46 (s, 1H), 7.13-7.10 (m, 2H), 5.19 (d, J=12.5 Hz, 1H), 3.07 (bs, 3H), 2.55 (bs, 3H). LCMS: 300 [M+H]. Calc. for C16H14FN3O2: C, 64.21; H, 4.71; N, 14.04. Found C, 64.22; H, 4.31; N, 14.10.